Trial Outcomes & Findings for Radiation Therapy Compared With Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Primary Central Nervous System (CNS) Germ Cell Tumor (NCT NCT00085098)

Last Updated: 2018-09-07

Results Overview

Data will be summarized as number of patients in the following categories at the time of data cutoff for analyses of 3-year EFS: 1)Experienced a qualifying event (QE) (see below);2)Event-free through 3 years of follow-up;3)Event-free until data cutoff (if less than 3 years of follow-up);4)Withdrew from study;5)Lost to follow-up. QEs: 1)disease progression, defined as increase \>= 40% in tumor volume or \>= 25% in tumor area of target lesions;2)development of new lesions;3)occurrence of a second malignant neoplasm, defined as a malignancy with different histological type from trial-qualifying diagnosis;4)death from any cause. Stat. analyses will be based on time from enrollment to the earliest of: 1)occurrence of any of the QEs;2)withdrawal from study or lost to follow-up;3)completion of three years of follow-up event-free;4)data cutoff for completion of the statistical analyses for the protocol's primary objective. NOTE: Reported data are through May 2009 (see Caveats section).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

24 participants

Primary outcome timeframe

Study enrollment until date of earliest qualifying event (QE), date last known to be QE-free if the patient is followed for less than three years and is QE-free at the time of analysis, or 3 years if the patient is QE-free at 3 years

Results posted on

2018-09-07

Participant Flow

Participant milestones

Participant milestones
Measure	Regimen A (Radiotherapy Only) Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) Courses 1,2:Patients (PTS) receive carboplatin IV over 1 hour on days 1-2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, PTS with complete response (CR) undergo low-dose radiation therapy 5 days a week for 5 weeks. PTS with minimal residual disease (MRD), a PR, or stable disease (SD) receive chemotherapy courses 3,4. Courses 3,4:PTS receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2-3 and filgrastim (G-CSF) subcutaneous (SC) or IV on day 4 continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. PTS achieving a CR or MRD proceed to reduced-dose radiotherapy. PTS with a partial response (PR), SD or progressive disease (PD) are restaged and may undergo standard radiation therapy as in regimen A.Reduced-dose radiation therapy: Within 6 weeks of starting course 4, PTS undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks.
Overall Study STARTED	11	13
Overall Study COMPLETED	10	11
Overall Study NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Regimen A (Radiotherapy Only) Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) Courses 1,2:Patients (PTS) receive carboplatin IV over 1 hour on days 1-2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, PTS with complete response (CR) undergo low-dose radiation therapy 5 days a week for 5 weeks. PTS with minimal residual disease (MRD), a PR, or stable disease (SD) receive chemotherapy courses 3,4. Courses 3,4:PTS receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2-3 and filgrastim (G-CSF) subcutaneous (SC) or IV on day 4 continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. PTS achieving a CR or MRD proceed to reduced-dose radiotherapy. PTS with a partial response (PR), SD or progressive disease (PD) are restaged and may undergo standard radiation therapy as in regimen A.Reduced-dose radiation therapy: Within 6 weeks of starting course 4, PTS undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks.
Overall Study Withdrawal by Subject	0	1
Overall Study Ineligible	1	1

Baseline Characteristics

Radiation Therapy Compared With Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Primary Central Nervous System (CNS) Germ Cell Tumor

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Regimen A (Radiotherapy Only) n=11 Participants Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) n=13 Participants Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks	Total n=24 Participants Total of all reporting groups
Age, Categorical <=18 years	10 Participants n=99 Participants	13 Participants n=107 Participants	23 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Age, Categorical >=65 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Sex: Female, Male Female	4 Participants n=99 Participants	1 Participants n=107 Participants	5 Participants n=206 Participants
Sex: Female, Male Male	7 Participants n=99 Participants	12 Participants n=107 Participants	19 Participants n=206 Participants
Region of Enrollment United States	10 participants n=99 Participants	8 participants n=107 Participants	18 participants n=206 Participants
Region of Enrollment Australia	1 participants n=99 Participants	4 participants n=107 Participants	5 participants n=206 Participants
Region of Enrollment Switzerland	0 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants

PRIMARY outcome

Timeframe: Study enrollment until date of earliest qualifying event (QE), date last known to be QE-free if the patient is followed for less than three years and is QE-free at the time of analysis, or 3 years if the patient is QE-free at 3 years

Population: By protocol design, all eligible patients were considered in the evaluation of primary study aim. Two (2) patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in the evaluation for the primary outcome measure.

Outcome measures

Outcome measures
Measure	Regimen A (Radiotherapy Only) n=10 Participants Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) n=12 Participants Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks
Event-free Survival Withdrew from study prior to 3 years of follow-up	0 participants	0 participants
Event-free Survival Lost to follow-up prior to 3 years of follow-up	0 participants	0 participants
Event-free Survival Experienced a qualifying event	1 participants Interval 43.0 to 98.0	1 participants Interval 54.0 to 99.0
Event-free Survival Event-free through 3 years of follow-up	0 participants	0 participants
Event-free Survival Event-free at data cutoff (if < 3 years follow-up)	9 participants	11 participants

SECONDARY outcome

Timeframe: 5 years from beginning of treatment

Population: Patients who were treated in Regimen B and had at least one response assessment are included in this analysis. One patient in Regimen B withdrew from the pre-Radiotherapy chemotherapy and did not have any response assessment were not included for the response analysis.

To assess the complete response rate to pre-radiotherapy chemotherapy (Reg B only). Response was determined after completing 2-4 cycles of chemotherapy on Reg B. Complete Response (CR) is defined as disappearance of all target lesions.

Outcome measures

Outcome measures
Measure	Regimen A (Radiotherapy Only) n=11 Participants Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks
Number of Participants With a Response to Regimen B	8 Participants	—

SECONDARY outcome

Timeframe: From the beginning of treatment, assessed up to 5 years

Population: Patients who received any pre-radiotherapy chemotherapy in Regimen B

The analysis of toxicity will focus on estimating the rates of key acute and subacute toxicity occurring during the first induction chemotherapy. The list of toxicities of interest include Anemia or Febrile Neutropenia; Nausea or Vomiting; Infections and Infestations; Neutrophil or White blood count decrease; and Hypokalemia or Hyponatremia

Outcome measures

Outcome measures
Measure	Regimen A (Radiotherapy Only) n=12 Participants Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks
Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Anemia or Febrile Neutropenia	2 Participants	—
Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Nausea or Vomiting	2 Participants	—
Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Infections and Infestations	2 Participants	—
Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Neutorphil or White blood count decrease	7 Participants	—
Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Hypokalemia or Hyponatremia	3 Participants	—

SECONDARY outcome

Timeframe: 2 years from beginning of treatment

Population: All eligible patients who also successfully completed therapy and were assessed for quality of life and neurocognitive outcome.

The primary endpoints for QOL and NP assessments will be the global scale value from each of these instruments at the two-year time point. Analyses of subscales (if they exist) and of assessments at other times will be of secondary interest. It is assumed that scale values are standardized to a reference normal population. The scores range from 0 to 100 with higher score reflecting better QoL or neurocognitive assessment.

Outcome measures

Outcome measures
Measure	Regimen A (Radiotherapy Only) n=10 Participants Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) n=11 Participants Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks
Quality of Life (QOL) and Neurocognitive Assessment (NP) Overall IQ Score	98.60 Scores on a scale Standard Deviation 17.95	92.43 Scores on a scale Standard Deviation 6.27
Quality of Life (QOL) and Neurocognitive Assessment (NP) Self Report Score-Internalizing Problems	41.00 Scores on a scale Standard Deviation 2.83	42.50 Scores on a scale Standard Deviation 5.51
Quality of Life (QOL) and Neurocognitive Assessment (NP) Self Report Score-Personal Adjustment Strengths	51.50 Scores on a scale Standard Deviation 2.12	60.50 Scores on a scale Standard Deviation 3.32
Quality of Life (QOL) and Neurocognitive Assessment (NP) Parent Report QoL Total Score	88.04 Scores on a scale Standard Deviation 6.15	79.35 Scores on a scale Standard Deviation 6.15
Quality of Life (QOL) and Neurocognitive Assessment (NP) Self Report QoL Total Score	95.65 Scores on a scale Standard Deviation NA The Reg A only has 1 pt with Self Report QoL Total Score, so the Standard Deviation cannot be estimated.	90.76 Scores on a scale Standard Deviation 0.76
Quality of Life (QOL) and Neurocognitive Assessment (NP) Self Report Score-Emotional Problems	44.00 Scores on a scale Standard Deviation 2.83	42.00 Scores on a scale Standard Deviation 4.55

Adverse Events

Regimen A (Radiotherapy Only)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Regimen B (Chemotherapy Plus Radiotherapy)

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Results Coordinator

Children's Oncology Group

Phone: (626) 447-0064

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Regimen A (Radiotherapy Only) n=10 participants at risk Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks.	Regimen B (Chemotherapy Plus Radiotherapy) n=12 participants at risk Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below. Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A. Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks
Investigations Alanine aminotransferase increased	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	16.7% 2/12 • Number of events 2 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Immune system disorders Anaphylaxis	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Blood and lymphatic system disorders Anemia	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	16.7% 2/12 • Number of events 2 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Metabolism and nutrition disorders Anorexia	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	0.00% 0/12 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Metabolism and nutrition disorders Dehydration	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	0.00% 0/12 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
General disorders Fatigue	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Investigations GGT increased	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Metabolism and nutrition disorders Hyperglycemia	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Metabolism and nutrition disorders Hypernatremia	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Metabolism and nutrition disorders Hypokalemia	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	16.7% 2/12 • Number of events 2 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	25.0% 3/12 • Number of events 3 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Infections and infestations "Infections and infestations - Other, specify"	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	16.7% 2/12 • Number of events 2 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Investigations Lymphocyte count decreased	30.0% 3/10 • Number of events 3 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	33.3% 4/12 • Number of events 4 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Gastrointestinal disorders Nausea	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) "Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify"	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	8.3% 1/12 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Investigations Neutrophil count decreased	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	75.0% 9/12 • Number of events 9 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Nervous system disorders Peripheral motor neuropathy	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	0.00% 0/12 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Investigations Platelet count decreased	0.00% 0/10 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	58.3% 7/12 • Number of events 7 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Gastrointestinal disorders Vomiting	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	16.7% 2/12 • Number of events 2 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.
Investigations White blood cell decreased	10.0% 1/10 • Number of events 1 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.	41.7% 5/12 • Number of events 5 • During protocol therapy; six months (maximum). All eligible patients were considered in the evaluation of adverse events (AEs). Two patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in AE reporting. Systematic assessment was performed according to protocol-directed schedule of assessments, and as clinically indicated.