Ovarian Neoplasms
Conditions
Brief summary
This is a Phase II, randomized, multi-centre study aiming at comparing the efficacy of Olaparib and Cediranib vs. weekly Paclitaxel in terms of progression free survival (PFS) in platinum refractory or resistant recurrent ovarian cancer. Patients will be randomised in a 1:1:1 ratio to three treatment arms: * Arm A: Paclitaxel 80 mg/mq every week * Arm B: Cediranib 20 mg/day + Olaparib 600 mg / day (i.e. 300 mg BD) given every day * Arm C: Cediranib 20 mg/day given 5 days per weeks + Olaparib 600 mg / day (i.e. 300 mg BD) given 7 days per weeks
Detailed description
Both the experimental arms (Arm B and C) will be compared with Arm A in terms of PFS. If both superior to the control (Arm A), they will be compared in terms of gastrointestinal safety.
Interventions
DRUGPaclitaxel
Comparator active compound
DRUGCediranib
Experimental compound
DRUGOlaparib
Experimental compound
Sponsors
AstraZeneca
Mario Negri Institute for Pharmacological Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients affected by pathologically confirmed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. 2. Relapsed/progressive disease within 6 months from last platinum-based chemotherapy (platinum resistant/refractory disease). 3. Any line of treatment (after the first). 4. Any last chemotherapy line, including Paclitaxel, that should have been administered at least 6 months before the study beginning. 5. Patients must be women \> 18 years of age. 6. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * Haemoglobin ≥ 10.0 g/dL and no blood transfusions in the 28 days prior to entry/randomization - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * White blood cells (WBC) \> 3x109/L * Platelet count ≥ 100 x 109/L * Total bilirubin ≤ 1.5 x institutional Upper Limit of Normal (ULN) * AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional Upper Limit of Normal, unless liver metastases are present in which case it must be ≤ 5x ULN * Creatinine clearance estimated using the Cockcroft-Gault equation ≥51 mL/min,. 7. ECOG performance status 0-1. 8. Patients must have a life expectancy ≥ 16 weeks. 9. Evidence of non-childbearing status for women of childbearing potential (negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1 or postmenopausal women. Postmenopausal status is defined as: * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments * LH and FSH levels in the post-menopausal range for women under 50 * Radiation-induced oophorectomy with last menses \>1 year ago, * Chemotherapy-induced menopause with \>1 year interval since last menses * Surgical sterilization (bilateral oophorectomy or hysterectomy) 10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up. 11. At least one lesion (measurable as defined by RECIST 1.1) that can be accurately assessed by CT scan or MRI with Chest X-ray at baseline and follow up visits. 12. BRCA1-2 mutation status known. In case of BRCA status unknown, the BRCA test must be performed before the randomization or, if not feasible, within the end-of the study treatment. 13. Provision of informed consent prior to any study specific procedures. In case of patients unable to give written informed consent, is necessary to have the subject or legal representative sign, but in any case a witness must be present and sign and date with the person providing informed consent.
Exclusion criteria
1. Any previous treatment with a PARP inhibitor, including Olaparib. 2. Prior treatment with Cediranib (previous bevacizumab or other antiangiogenic drugs are allowed) 3. Previous progression to weekly Paclitaxel 4. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years 5. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug. 6. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting Olaparib is 2 weeks. 7. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting Olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 8. Persistent toxicities (\>=CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy. 9. Resting ECG with QTc \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. 10. Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein \< 1.5g in a 24 hr period or urine protein/creatinine ratio \< 1.5. 11. A history of poorly controlled hypertension or resting blood pressure \>150/100 mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy (measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2-minute intervals and averaged. If the first two diastolic readings differ by more than 5 mmHg, then an additional reading should be obtained and averaged). 12. Blood transfusions within 28 days prior to study start. 13. Features suggestive of Myelodysplastic syndrome or Acute myeloid leukemia (MDS/AML) on peripheral blood smear. 14. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment. 15. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 16. Patients considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent. 17. Patients unable to swallow medications and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 18. Breast feeding women. 19. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy. 20. Patients with known active hepatic disease (i.e., Hepatitis B or C). 21. Patients with a known hypersensitivity to Olaparib, Cediranib or any of the excipients of the products. 22. Patients with a known hypersensitivity to Paclitaxel. 23. Patients with uncontrolled seizures. 24. History of abdominal fistula or gastrointestinal perforation. 25. Prior gastrectomy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Progression Free Survival (PFS) | An average of 30 months for each participant | PFS is defined as time from randomization to the date of first progression or death for any cause, whichever comes first. Progression was established as the radiological disease progression according to RECIST 1.1 (as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions) or to clinical assessment in case radiological evaluation is not feasible due to clinical condition. |
| Safety: Number of Evacuations Per Day | Evacuation were collected daily for the first four weeks of treatment of experimental drugs | Number of evacuations per day used as an index of gastro-intestinal toxicity profile of experimental drugs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Overall Survival (OS) | Up to one year after the last patient enrolled | OS is defined as time from randomization to the date of death for any cause |
| Efficacy: Quality of Life | Up to sixth month of study treatment | Quality of Life evaluated by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire |
| Safety: Maximum Toxicity Grade | Up to 30 days after the end of treatment | Maximum toxicity grade experienced by each patient, for each toxicity, according to NCI-CTCAE v. 4.03 |
| Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Adverse events were collected at the end of each cycle for the duration of treatment for each participant (an average of 3.5 months) and following 30 days after the end of treatment. | Number of patients experiencing grade 3-4 toxicity for each toxicity according to NCI-CTCAE v. 4.03 |
| Safety: Type, Frequency and Nature of SAEs | Up to 30 days after the end of treatment | Type, frequency and nature of SAEs, according to NCI-CTCAE v. 4.03 |
| Efficacy: Objective Response Rate (ORR) | Disease assessments were scheduled every 8 weeks (+/- 1 week) from randomization for all treatment duration (an average of 3.5 months). | Percentage of patients with an objective response as determined by RECIST 1.1 |
| Safety: Number of Patients With at Least a SUSAR | Up to 30 days after the end of treatment | Number of patients with at least a SUSAR, according to NCI-CTCAE v. 4.03 |
| Compliance: Number of Administered Cycles | Up to one year after the last patient enrolled | The endpoint for compliance is the number of administered cycles. |
| Compliance: Reasons for Discontinuation and Treatment Modification | Up to one year after the last patient enrolled | The endpoints for compliance are the reasons for discontinuation and treatment modification. |
| Compliance: Dose Intensity | Up to one year after the last patient enrolled | Entire dose administered during treatment |
| Safety: Number of Patients With at Least a SAE; Patients With at Least a SADR | Up to 30 days after the end of treatment | Number of patients with at least a SAE; patients with at least a SADR, according to NCI-CTCAE v. 4.03 |
| Efficacy: PFS2 | Up to one year after the last patient enrolled | PFS2 is defined as time from first progression to the date of second progression or death for any cause, whichever comes first. |
Countries
Italy
Participant flow
Recruitment details
The study was approved and activated in 7 experimental sites. The enrolment was closed on 18th October 2018 with the inclusion of 123 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm A Intravenous administration of weekly Paclitaxel (dosage: 80 mg/mq) for a maximum of 6 cycles. Cycle is defined as 4 weeks.
Paclitaxel: Comparator active compound | 41 |
| Arm B Oral administration of two experimental drugs:
* Cediranib 20 mg/day given 7 days per week
* Olaparib 600 mg / day (i.e. 300 mg twice a day) 7 days per week until progression, unacceptable toxicity, patient or physician decision to discontinue or death.
Cediranib: Experimental compound
Olaparib: Experimental compound | 41 |
| Arm C Oral administration of two experimental drugs:
* Cediranib 20 mg/day given 5 days per week
* Olaparib 600 mg / day (i.e. 300 mg twice a day) 7 days per week until progression, unacceptable toxicity, patient or physician decision to discontinue or death.
Cediranib: Experimental compound
Olaparib: Experimental compound | 41 |
| Total | 123 |
Baseline characteristics
| Characteristic | Arm A | Total | Arm C | Arm B |
|---|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 8.1 | 61.7 years STANDARD_DEVIATION 9.7 | 61.4 years STANDARD_DEVIATION 9.4 | 61.0 years STANDARD_DEVIATION 11.4 |
| BRCA mutated | 4 Participants | 15 Participants | 4 Participants | 7 Participants |
| Last Platinum Free interval | 3.0 months STANDARD_DEVIATION 2.3 | 2.6 months STANDARD_DEVIATION 2.2 | 2.3 months STANDARD_DEVIATION 2.4 | 2.5 months STANDARD_DEVIATION 1.9 |
| Previous Chemotherapy lines | 2.6 lines STANDARD_DEVIATION 1.2 | 2.9 lines STANDARD_DEVIATION 1.3 | 2.9 lines STANDARD_DEVIATION 1.2 | 3.1 lines STANDARD_DEVIATION 1.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 36 Participants | 114 Participants | 40 Participants | 38 Participants |
| Sex: Female, Male Female | 41 Participants | 123 Participants | 41 Participants | 41 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 24 / 28 | 31 / 41 | 34 / 41 |
| other Total, other adverse events | 16 / 28 | 36 / 41 | 34 / 41 |
| serious Total, serious adverse events | 3 / 28 | 11 / 41 | 9 / 41 |
Outcome results
Primary
Efficacy: Progression Free Survival (PFS)
PFS is defined as time from randomization to the date of first progression or death for any cause, whichever comes first. Progression was established as the radiological disease progression according to RECIST 1.1 (as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions) or to clinical assessment in case radiological evaluation is not feasible due to clinical condition.
Time frame: An average of 30 months for each participant
Population: Intention to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Efficacy: Progression Free Survival (PFS) | 3.1 months |
| Arm B | Efficacy: Progression Free Survival (PFS) | 5.6 months |
| Arm C | Efficacy: Progression Free Survival (PFS) | 3.8 months |
p-value: 0.26590% CI: [0.5, 1.14]cox model
p-value: 0.90490% CI: [0.68, 1.55]cox- model
Primary
Safety: Number of Evacuations Per Day
Number of evacuations per day used as an index of gastro-intestinal toxicity profile of experimental drugs
Time frame: Evacuation were collected daily for the first four weeks of treatment of experimental drugs
Population: No primary safety analysis in terms of gastrointestinal events between continuous and intermittent arm was done because neither experimental arm showed any superiority in PFS over the control arm.
Secondary
Compliance: Dose Intensity
Entire dose administered during treatment
Time frame: Up to one year after the last patient enrolled
Secondary
Compliance: Number of Administered Cycles
The endpoint for compliance is the number of administered cycles.
Time frame: Up to one year after the last patient enrolled
Secondary
Compliance: Reasons for Discontinuation and Treatment Modification
The endpoints for compliance are the reasons for discontinuation and treatment modification.
Time frame: Up to one year after the last patient enrolled
Secondary
Efficacy: Objective Response Rate (ORR)
Percentage of patients with an objective response as determined by RECIST 1.1
Time frame: Disease assessments were scheduled every 8 weeks (+/- 1 week) from randomization for all treatment duration (an average of 3.5 months).
Population: ORR population: patients in the ITT population who received at least one dose of study treatment and had at least one radiological assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Efficacy: Objective Response Rate (ORR) | 9 participants |
| Arm B | Efficacy: Objective Response Rate (ORR) | 6 participants |
| Arm C | Efficacy: Objective Response Rate (ORR) | 4 participants |
Secondary
Efficacy: Overall Survival (OS)
OS is defined as time from randomization to the date of death for any cause
Time frame: Up to one year after the last patient enrolled
Secondary
Efficacy: PFS2
PFS2 is defined as time from first progression to the date of second progression or death for any cause, whichever comes first.
Time frame: Up to one year after the last patient enrolled
Secondary
Efficacy: Quality of Life
Quality of Life evaluated by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire
Time frame: Up to sixth month of study treatment
Secondary
Safety: Maximum Toxicity Grade
Maximum toxicity grade experienced by each patient, for each toxicity, according to NCI-CTCAE v. 4.03
Time frame: Up to 30 days after the end of treatment
Secondary
Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity
Number of patients experiencing grade 3-4 toxicity for each toxicity according to NCI-CTCAE v. 4.03
Time frame: Adverse events were collected at the end of each cycle for the duration of treatment for each participant (an average of 3.5 months) and following 30 days after the end of treatment.
Population: safety population: randomized patients receiving at least one dose of study drugs
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Bone marrow hypocellular grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Myelodysplastic syndrome grade 5 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Fatigue grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Anemia grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Anorexia grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Sepsis grade 5 | 1 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Diarrhea grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | White blood cells decreased grade≥3 | 1 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Neutrophil count decreased grade≥3 | 2 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Thromboembolic event grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Platelet count decreased grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Palmar-plantar erythrodysesthesia syndrome grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Mucositis oral grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Hypertension grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Pneumonitis grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Nausea grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Febrile neutropenia grade≥3 | 0 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Peripheral motor neuropathy grade≥3 | 1 Participants |
| Arm A | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Vomiting grade≥3 | 0 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Palmar-plantar erythrodysesthesia syndrome grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Anemia grade≥3 | 4 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Bone marrow hypocellular grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Febrile neutropenia grade≥3 | 0 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Diarrhea grade≥3 | 2 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Mucositis oral grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Nausea grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Vomiting grade≥3 | 0 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Fatigue grade≥3 | 4 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Sepsis grade 5 | 0 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Neutrophil count decreased grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Platelet count decreased grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | White blood cells decreased grade≥3 | 0 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Anorexia grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Myelodysplastic syndrome grade 5 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Peripheral motor neuropathy grade≥3 | 0 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Pneumonitis grade≥3 | 1 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Hypertension grade≥3 | 5 Participants |
| Arm B | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Thromboembolic event grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Anorexia grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Vomiting grade≥3 | 2 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Thromboembolic event grade≥3 | 1 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Myelodysplastic syndrome grade 5 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Nausea grade≥3 | 3 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Hypertension grade≥3 | 6 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Peripheral motor neuropathy grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Mucositis oral grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Anemia grade≥3 | 6 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Pneumonitis grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Diarrhea grade≥3 | 1 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Neutrophil count decreased grade≥3 | 1 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Febrile neutropenia grade≥3 | 1 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Platelet count decreased grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Sepsis grade 5 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Palmar-plantar erythrodysesthesia syndrome grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | White blood cells decreased grade≥3 | 0 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Fatigue grade≥3 | 5 Participants |
| Arm C | Safety: Number of Patients Experiencing Grade 3-4 Toxicity for Each Toxicity | Bone marrow hypocellular grade≥3 | 0 Participants |
Secondary
Safety: Number of Patients With at Least a SAE; Patients With at Least a SADR
Number of patients with at least a SAE; patients with at least a SADR, according to NCI-CTCAE v. 4.03
Time frame: Up to 30 days after the end of treatment
Secondary
Safety: Number of Patients With at Least a SUSAR
Number of patients with at least a SUSAR, according to NCI-CTCAE v. 4.03
Time frame: Up to 30 days after the end of treatment
Secondary
Safety: Type, Frequency and Nature of SAEs
Type, frequency and nature of SAEs, according to NCI-CTCAE v. 4.03
Time frame: Up to 30 days after the end of treatment