Trial Outcomes & Findings for Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus (NCT NCT01378377)

Last Updated: 2018-07-30

Results Overview

DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade \>=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration \<= 48 hours and alopecia; Grade 4 neutropenia of \>5 days duration or febrile neutropenia of \>1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption \>2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

33 participants

Primary outcome timeframe

Up to 21 Days (within Cycle 1)

Results posted on

2018-07-30

Participant Flow

First/last subject (informed consent): 27 May 2011/23 August 2012. Last subject completed: 23 February 2012; Subjects randomized at 2 centers in United States.

46 screened for eligibility; 13 were excluded (mainly non-fulfillment of inclusion or exclusion criteria). 33 subjects were enrolled and treated in the study.

Participant milestones

Participant milestones
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.
Overall Study STARTED	4	23	6
Overall Study COMPLETED	4	23	6
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=23 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Total n=33 Participants Total of all reporting groups
Age, Continuous	63.3 years STANDARD_DEVIATION 11.30 • n=99 Participants	57.9 years STANDARD_DEVIATION 14.09 • n=107 Participants	55.5 years STANDARD_DEVIATION 6.19 • n=206 Participants	58.1 years STANDARD_DEVIATION 12.61 • n=7 Participants
Sex: Female, Male Female	2 Participants n=99 Participants	16 Participants n=107 Participants	4 Participants n=206 Participants	22 Participants n=7 Participants
Sex: Female, Male Male	2 Participants n=99 Participants	7 Participants n=107 Participants	2 Participants n=206 Participants	11 Participants n=7 Participants

PRIMARY outcome

Timeframe: Up to 21 Days (within Cycle 1)

Population: The dose escalation analysis set included all the subjects who received at least 80% of the planned doses of each treatment (pimasertib and temsirolimus) in the first cycle of treatment or who experienced DLT during the first cycle of treatment regardless of the received amount of drug.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=3 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=17 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Number of Subjects With Dose Limiting Toxicities (DLTs)	0 subjects	7 subjects	2 subjects	—

SECONDARY outcome

Timeframe: From the start of the trial treatment until data cut-off date (23 February 2012)

Population: The safety analysis set included all the subjects who received at least one administration of trial medication.

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. The TEAEs were those events that occur between first dose of trial treatment and up to 30 days after last dose of the trial treatment that were absent before treatment or that worsened relative to pretreatment state.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=23 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Number of Subjects With Treatment-emergent Adverse Events (TEAEs)	4 subjects	23 subjects	6 subjects	—

SECONDARY outcome

Timeframe: Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=15 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=5 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Maximum Plasma Concentration (Cmax) of Pimasertib DDI: Day 1	185.2 nanogram/milliliter Interval 87.38 to 266.5	193.5 nanogram/milliliter Interval 97.24 to 326.5	—	—
Maximum Plasma Concentration (Cmax) of Pimasertib DDI: Day 9	131 nanogram/milliliter Interval 68.75 to 190.5	192.1 nanogram/milliliter Interval 63.8 to 406.0	—	—
Maximum Plasma Concentration (Cmax) of Pimasertib Non-DDI: Day 8	—	—	197.6 nanogram/milliliter Interval 73.75 to 317.3	308.1 nanogram/milliliter Interval 157.3 to 460.0

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=10 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Maximum Plasma Concentration (Cmax) of Temsirolimus DDI: Day 9	457.5 nanogram/milliliter Interval 361.6 to 578.1	505.3 nanogram/milliliter Interval 396.8 to 591.4	—	—
Maximum Plasma Concentration (Cmax) of Temsirolimus DDI: Day 16	281.1 nanogram/milliliter Interval 13.21 to 636.4	511.8 nanogram/milliliter Interval 184.6 to 575.9	—	—
Maximum Plasma Concentration (Cmax) of Temsirolimus Non-DDI: Day 8	—	—	489.9 nanogram/milliliter Interval 391.9 to 525.5	480.9 nanogram/milliliter Interval 323.3 to 589.7

SECONDARY outcome

Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=15 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=5 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib DDI: Day 1	1 hour Interval 0.5333 to 2.0	1.5 hour Interval 0.0 to 4.0	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib DDI: Day 9	2.3 hour Interval 0.9167 to 4.033	1.133 hour Interval 0.5 to 2.667	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib Non-DDI: Day 8	—	—	1.5 hour Interval 1.0 to 3.967	0.5833 hour Interval 0.5 to 3.0

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=10 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus DDI: Day 9	0.7417 hour Interval 0.5167 to 1.0	0.5667 hour Interval 0.5 to 1.017	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus DDI: Day 16	0.9333 hour Interval 0.5 to 24.05	0.5 hour Interval 0.5 to 1.55	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus Non-DDI: Day 8	—	—	0.5 hour Interval 0.5 to 0.55	0.55 hour Interval 0.4333 to 0.5833

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

The AUCtau was defined as the area under the concentration curve divided by the dosing interval. AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=14 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib DDI: AUCtau: Day 9	628 hour*nanogram/milliliter Interval 435.6 to 1338.0	805 hour*nanogram/milliliter Interval 264.3 to 1623.0	—	—
Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib Non-DDI: AUCtau: Day 8	—	—	706 hour*nanogram/milliliter Interval 333.8 to 2548.0	1402 hour*nanogram/milliliter Interval 922.2 to 1735.0
Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib DDI: AUC0-inf: Day 1	573.2 hour*nanogram/milliliter Interval 393.5 to 1703.0	828.6 hour*nanogram/milliliter Interval 373.3 to 1310.0	—	—

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure;"Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=10 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=5 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus DDI: Day 9	2452 hour*nanogram/milliliter Interval 1670.0 to 4440.0	2130 hour*nanogram/milliliter Interval 1534.0 to 3642.0	—	—
Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus DDI: Day 16	2006 hour*nanogram/milliliter Interval 1174.0 to 2837.0	2743 hour*nanogram/milliliter Interval 1977.0 to 3219.0	—	—
Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus Non-DDI: Day 8	—	—	4026 hour*nanogram/milliliter Interval 2386.0 to 4783.0	2194 hour*nanogram/milliliter Interval 1324.0 to 2483.0

SECONDARY outcome

Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=14 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Apparent Terminal Half-life (t1/2) of Pimasertib DDI: Day 1	5.915 hour Interval 4.718 to 6.652	5.886 hour Interval 2.504 to 20.25	—	—
Apparent Terminal Half-life (t1/2) of Pimasertib DDI: Day 9	6.08 hour Interval 2.101 to 11.17	5.896 hour Interval 2.013 to 23.86	—	—
Apparent Terminal Half-life (t1/2) of Pimasertib Non-DDI: Day 8	—	—	7.746 hour Interval 5.625 to 9.993	5.712 hour Interval 2.365 to 8.656

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. N=subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=10 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=5 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Apparent Terminal Half-life (t1/2) of Temsirolimus DDI: Day 9	25.57 hour Interval 10.39 to 54.46	13.2 hour Interval 9.237 to 34.92	—	—
Apparent Terminal Half-life (t1/2) of Temsirolimus DDI: Day 16	20.62 hour Interval 12.97 to 28.27	19.14 hour Interval 13.54 to 25.82	—	—
Apparent Terminal Half-life (t1/2) of Temsirolimus Non-DDI: Day 8	—	—	29.08 hour Interval 26.14 to 44.14	10.42 hour Interval 9.192 to 13.76

SECONDARY outcome

Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure;"Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Clearance (CL) of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The CL obtained after oral dose (CL/F) was influenced by the fraction of the dose absorbed (bioavailability). Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=14 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib DDI: Day 1	81.25 liter/hour Interval 26.42 to 114.4	54.36 liter/hour Interval 34.36 to 120.6	—	—
Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib DDI: Day 9	71.99 liter/hour Interval 33.63 to 103.3	55.9 liter/hour Interval 27.73 to 170.3	—	—
Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib Non-DDI: Day 8	—	—	64.31 liter/hour Interval 17.66 to 134.8	53.6 liter/hour Interval 43.22 to 81.33

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

The clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=10 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=5 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus DDI: Day 9	5.378 liter/hour Interval 2.815 to 7.486	11.73 liter/hour Interval 6.863 to 16.29	—	—
Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus DDI: Day 16	7.528 liter/hour Interval 4.406 to 10.65	9.292 liter/hour Interval 7.766 to 12.64	—	—
Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus Non-DDI: Day 8	—	—	6.284 liter/hour Interval 5.227 to 10.48	11.39 liter/hour Interval 10.07 to 18.89

SECONDARY outcome

Timeframe: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure; "Number Analyzed" signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.

Volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The Vz after oral dose (Vz/F) was influenced by the fraction absorbed. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=14 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=6 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Apparent Volume of Distribution (Vz/F) of Pimasertib DDI: Day 1	691.3 liter Interval 210.3 to 923.0	536.5 liter Interval 199.4 to 1450.0	—	—
Apparent Volume of Distribution (Vz/F) of Pimasertib DDI: Day 9	517.6 liter Interval 274.4 to 1080.0	519.5 liter Interval 157.3 to 1768.0	—	—
Apparent Volume of Distribution (Vz/F) of Pimasertib Non-DDI: Day 8	—	—	760.6 liter Interval 143.3 to 1840.0	416.5 liter Interval 190.4 to 745.5

SECONDARY outcome

Timeframe: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1

The Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.

Outcome measures

Outcome measures
Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=10 Participants Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=4 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) n=5 Participants Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. Subjects were not analyzed for drug-drug interaction.
Volume of Distribution (Vz) of Temsirolimus DDI: Day 9	152 liter Interval 99.01 to 326.1	244.5 liter Interval 142.2 to 505.4	—	—
Volume of Distribution (Vz) of Temsirolimus DDI: Day 16	189.5 liter Interval 179.6 to 199.3	233 liter Interval 216.1 to 394.4	—	—
Volume of Distribution (Vz) of Temsirolimus Non-DDI: Day 8	—	—	309.7 liter Interval 203.6 to 471.3	172.9 liter Interval 133.5 to 375.0

SECONDARY outcome

Timeframe: From the start of the trial treatment until data cut-off date (23 February 2012)

Population: Data was not evaluated for this outcome as the subjects did not met the minimum criteria duration for the evaluation of the outcome measure due to the early termination of the trial

Disease control is defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) \>=12 weeks), based on tumor assessments as determined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. CR: The disappearance of all lesions and normalization of tumor marker level. PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline. SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: DDI cohorts: Days 1, 9 and 10 of Cycle 1; Non-DDI cohorts: Days 1, 8 and 9 of Cycle 1

Population: As the trial was terminated early due to toxicities observed with the combination of pimasertib and temsirolimus, it was decided as per plan not to evaluate the biomarker data for this study

During the first cycle (either Cycle 1 non-DDI or Cycle 1-DDI) blood samples will be collected for pharmacodynamic marker assessments by flow cytometry such as phospho-ERK and phospho- S6 activities in PBMCs

Outcome measures

Outcome data not reported

Adverse Events

Pimasertib 45 mg+Temsirolimus 12.5 mg

Serious events: 3 serious events

Other events: 4 other events

Deaths: 0 deaths

Pimasertib 45 mg+Temsirolimus 25 mg

Serious events: 17 serious events

Other events: 23 other events

Deaths: 0 deaths

Pimasertib 75 mg+Temsirolimus 25 mg

Serious events: 5 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Serono, a division of Merck KGaA

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Pimasertib 45 mg+Temsirolimus 12.5 mg n=4 participants at risk Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 45 mg+Temsirolimus 25 mg n=23 participants at risk Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.	Pimasertib 75 mg+Temsirolimus 25 mg n=6 participants at risk Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.
Eye disorders Visual impairment	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	13.0% 3/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Stomatitis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	8.7% 2/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	33.3% 2/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Nausea	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Vomiting	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Abdominal pain	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Abdominal pain lower	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Diarrhoea	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Enterocutaneous fistula	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Haematemesis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Gastrointestinal disorders Oesophagitis ulcerative	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
General disorders Pyrexia	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	13.0% 3/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Pneumonia	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	17.4% 4/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Abdominal wall abscess	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Cellulitis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Clostridial infection	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Clostridium difficile sepsis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Osteomyelitis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Pharyngitis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Pulmonary sepsis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Pyelonephritis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	16.7% 1/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Sepsis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Infections and infestations Urinary tract infection	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Injury, poisoning and procedural complications Fall	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Injury, poisoning and procedural complications Procedural complication	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Investigations Blood creatine phosphokinase increased	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Metabolism and nutrition disorders Dehydration	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	8.7% 2/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	33.3% 2/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Nervous system disorders Balance disorder	25.0% 1/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Psychiatric disorders Mental status changes	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	8.7% 2/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Vascular disorders Extremity necrosis	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Vascular disorders Hypotension	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)
Vascular disorders Peripheral ischaemia	0.00% 0/4 • From the start of the trial treatment until data cut-off date (23 February 2012)	4.3% 1/23 • From the start of the trial treatment until data cut-off date (23 February 2012)	0.00% 0/6 • From the start of the trial treatment until data cut-off date (23 February 2012)