Trial Outcomes & Findings for Vorinostat and Trastuzumab in Treating Patients With Metastatic or Locally Recurrent Breast Cancer (NCT NCT00258349)

Last Updated: 2014-06-02

Results Overview

Tumor response is assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Response included complete response (CR) and partial response (PR). CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

16 participants

Primary outcome timeframe

Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy

Results posted on

2014-06-02

Participant Flow

The phase I portion of the study was activated on August 23, 2006, and completed on June 28, 2007. The phase II portion of the study then was activated, and suspended on October 4, 2007, terminated on August 27, 2009, with a final accrual of 16 patients by ECOG institutes.

Participant milestones

Participant milestones
Measure	Vorinostat +Trastuzumab Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat: 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle.
Overall Study STARTED	16
Overall Study HER2-positive by Central Review	10
Overall Study COMPLETED	16
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Vorinostat and Trastuzumab in Treating Patients With Metastatic or Locally Recurrent Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vorinostat +Trastuzumab n=16 Participants Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat: 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle.
Age, Continuous	54.1 years STANDARD_DEVIATION 10.3 • n=99 Participants
Sex: Female, Male Female	16 Participants n=99 Participants
Sex: Female, Male Male	0 Participants n=99 Participants
Region of Enrollment United States	16 participants n=99 Participants

PRIMARY outcome

Timeframe: Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy

Population: 10 eligible HER2-positive (by central review) patients

Outcome measures

Outcome measures
Measure	Vorinostat +Trastuzumab n=10 Participants Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle
Response Rate	0 percentage of participants Interval 0.0 to 26.0

SECONDARY outcome

Timeframe: Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy

Population: 10 eligible HER2-positive (by central review) patients

Tumor response is assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Disease progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). Time to progression is defined as time from registration to disease progression.

Outcome measures

Outcome measures
Measure	Vorinostat +Trastuzumab n=10 Participants Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle
Time to Progression	1.5 months Interval 1.3 to 3.7

SECONDARY outcome

Timeframe: Survival was assessed every 3 months for first 2 years from protocol entry, then every 6 months until 3 years from study entry

Population: 10 eligible HER2-positive (by central review) patients

Overall survival is defined as time from registration to death from any cause. Patients who were alive were censored as the last date of known alive.

Outcome measures

Outcome measures
Measure	Vorinostat +Trastuzumab n=10 Participants Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle
Overall Survival	9.3 months Interval 5.1 to 24.7

Adverse Events

Vorinostat +Trastuzumab (Phase II)

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Vorinostat +Trastuzumab (Phase I)

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Vorinostat +Trastuzumab (Phase II) n=9 participants at risk Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle	Vorinostat +Trastuzumab (Phase I) n=7 participants at risk phase I patients for identify maximum tolerated dose
Investigations Thrombocytopenia	22.2% 2/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	28.6% 2/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.

Other adverse events

Additional Information

Study Statistician

Eastern Cooperative Oncology Group (ECOG) Statistical Office

Phone: 617-632-3012

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Vorinostat +Trastuzumab (Phase II) n=9 participants at risk Trastuzumab: 6 mg/kg once on Day 1, infused over 90 minutes, every 3 weeks; Vorinostat 200 mg of SAHA orally twice a day, daily for 14 days out of a 21-day cycle	Vorinostat +Trastuzumab (Phase I) n=7 participants at risk phase I patients for identify maximum tolerated dose
Blood and lymphatic system disorders Anemia	33.3% 3/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	28.6% 2/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Leukopenia	22.2% 2/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Neutropenia	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Thrombocytopenia	22.2% 2/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Vascular disorders Hypotension	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
General disorders Fatigue	33.3% 3/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	42.9% 3/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Psychiatric disorders Insomnia	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Weight loss	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	28.6% 2/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Skin and subcutaneous tissue disorders Nail change	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Metabolism and nutrition disorders Anorexia	22.2% 2/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	42.9% 3/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Gastrointestinal disorders Constipation	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Metabolism and nutrition disorders Dehydration	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	28.6% 2/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Gastrointestinal disorders Diarrhea w/o prior colostomy	55.6% 5/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	71.4% 5/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Gastrointestinal disorders Nausea	33.3% 3/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	42.9% 3/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Gastrointestinal disorders Vomiting	33.3% 3/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	28.6% 2/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Creatinine increased	44.4% 4/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Metabolism and nutrition disorders Hyperglycemia	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	57.1% 4/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Metabolism and nutrition disorders Hypokalemia	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	28.6% 2/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Nervous system disorders Dizziness	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Respiratory, thoracic and mediastinal disorders Pneumonitis/pulmonary infiltrates	0.00% 0/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	14.3% 1/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Vascular disorders Hypertension	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Skin and subcutaneous tissue disorders Rash: acne/acneiform	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Gastrointestinal disorders Muco/stomatitis by exam, oral cavity	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Gastrointestinal disorders Taste disturbance	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Alkaline phosphatase increased	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Alanine aminotransferase (ALT) increased	22.2% 2/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Investigations Aspartate aminotransferase (AST) increased	22.2% 2/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Metabolism and nutrition disorders Hypocalcemia	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.
Metabolism and nutrition disorders Hyponatremia	11.1% 1/9 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.	0.00% 0/7 • For Phase I, toxicity was assessed once a week during Cycle 1 and at the end of each cycle for Cycles 2 and all subsequent cycles. For Phase II, assess toxicity at the end of every cycle (1 cycle = 21 Days) and 30 days after after the end of treatment.