| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRCA1 or BRCA2 mutation metastatic breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| BRCA1 or BRCA2 mutation metastatic breast cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000020826 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the progression-free survival of oral veliparib in combination with temozolomide or in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and locally recurrent or metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess overall survival, clinical benefit rate & objective response rate in those subjects treated with veliparib plus TMZ or treated with veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age.
2. Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic. Locally recurrent disease must not be amenable to surgical resection or radiation with curative intent.
3. Must have a documented deleterious BRCA1 or BRCA2 germline mutation. The investigator should ensure that the testing is consistent with local guidelines, and clinical practice, and that the
test uses either 1) direct DNA sequencing/multiplex ligation-dependent probe amplification (MLPA) or 2) a well-characterized methodology previously validated by sequencing, such as that
used to assess founder mutations. If testing has been performed by a laboratory other than Sponsor core laboratory, subjects may be enrolled but must be re-tested by Sponsor core laboratory for
confirmation of BRCA1 or BRCA2 germline mutations.
4. If HER2 positive (HER2 3+ by immunohistochemistry or amplification by fluorescence in situ hybridization [FISH > 2]), subjects must have received and progressed on at least one prior
standard HER2-directed therapy or the subject must be ineligible to receive anti-HER2 therapy.
5. Measurable or non-measurable (but radiologically evaluable disease per RECIST version 1.1 on computed tomography (CT) scan (within 28 days of C1D1) with at least one lesion outside previously irradiated areas.
6. ECOG Performance status of 0 to 2 (within 28 days of C1D1).
7. Adequate hematologic, renal, and hepatic function as detailed in the protocol.
8. Women of childbearing potential and men must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation and for 90 days
following completion of therapy. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation. To be considered of non-child bearing potential, postmenopausal women must be amenorrheic for at least 12 months or subjects must be surgically sterile.
- Total abstinence from sexual intercourse (for a minimum of one complete menstrual cycle prior to study drug administration);
- Vasectomized male subjects or vasectomized partner of female subjects;
- Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream);
- Intra-Uterine Device (IUD);
- Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 90 days following completion of therapy.
9. Capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to initiation of any screening or study-specific procedures. |
|
| E.4 | Principal exclusion criteria |
1. Received anticancer agent(s) or an investigational agent within 21days prior to C1D1 or radiotherapy within 28 days prior to C1D1. Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur, if administered at least 14 days prior to C1D1. Subjects experiencing a significant adverse effect or toxicity (Grade 3 or Grade 4), causally attributed to previous anticancer treatment that has not recovered to at least Grade 2 are excluded. Anticancer hormonal therapy must be stopped 7 days before starting C1D1. Subjects receiving bisphosphonates or denosumab are eligible.
2. More than 2 prior lines of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, capecitabine) for metastatic disease.
- Regimens received in the adjuvant/neoadjuvant setting or for locally recurrent breast cancer within the past 6 months will also be considered toward the maximum of 2 prior lines of therapy.
- A regimen will be considered a line of therapy if it includes a cytotoxic agent administered for the treatment of breast cancer more than 1 full cycle. Therapy administered for 1 full cycle or less will not be counted towards the number of lines of therapy unless the patient experienced progression of disease while on that therapy.
- Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal transduction agents (e.g., trastuzumab lapatinib, erlotinib, gefitinib, bevacizumab) are allowed and are not counted towards the prior line of therapy.
3. Prior treatment of breast cancer with temozolomide, a platinum agent, or a Poly-(ADP-ribose)-Polymerase (PARP)-inhibitor.
- Therapy with temozolomide, a platinum agent, or a PARP inhibitor administered for 1 full cycle or less will not be considered as prior therapy unless the patient experienced progression of disease while on that therapy.
4. Prior taxane therapy administered for the treatment of metastatic breast cancer disease with the below exceptions.
- Prior taxane therapy for metastatic breast cancer is allowed if the patient received ≤ 1 full cycle (i.e., within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; within 3 weeks for subjects receiving paclitaxel or docetaxel every 3 weeks) in the absence of progression or if taxane therapy for metastatic disease was > 12 months prior to C1D1.
- Use of taxanes as adjuvant therapy or to treat locally recurrent disease is permitted, if given more than 6 months prior to C1D1.
In all cases, the subject must be an appropriate candidate for paclitaxel therapy as per standard practice and per the investigator's discretion.
5. A history of or evidence of brain metastases or leptomeningeal disease. Subjects with symptoms to suggest central nervous system (CNS) metastases should have a brain MRI within 28 days of enrollment to confirm the absence of CNS metastases. Contrast CT is acceptable for subjects who are unable to undergo a brain MRI.
6. A history of uncontrolled seizure disorder.
7. Pre-existing neuropathy from any cause in excess of Grade 1.
8. Known history of allergic reactions to cremophor-paclitaxel.
9. Clinically significant uncontrolled condition(s).
- Active infection;
- Symptomatic congestive heart failure;
- Unstable angina pectoris or cardiac arrhythmia;
- Myocardial infarction within last 6 months;
- Psychiatric illness/social situations that would limit compliance with study requirements;
or
- Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.
10. A previous or concurrent cancer that is distinct in primary site or histology from metastatic breast cancer, except cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ
carcinoma of the bladder. Any cancer curatively treated greater than 3 years prior to entry is permitted. For these subjects, metastases must be histologically or cytologically confirmed to be
breast cancer.
11. Pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression Free Survival is defined as the number of days from the date the subject was randomized to the date the subject experienced a confirmed event of disease progression (as determined by the central imaging center), or to the date of death (all causes of mortality), if disease progression is not reached. |
|
| E.5.2 | Secondary end point(s) |
| Overall Survival, Clinical Benefit Rate and Objective Response Rate |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall Survival - number of days from randomization to date of death.
Clinical Benefit Rate - number of subjects who have at least stable disease or Non-CR/Non-PD through the end of Week 18. All intent to treat subjects will be included in the analysis.
Objective Response Rate - all subjects who have had at least one measurable lesion at baseline will be included in the objective response rate calculation
Chemotherapy-Induced Peripheral Neuropathy - scores from the EORTC QLQ-CIPN20 instrument will be evaluated per published literature. In addition, the incidence of treatment-emergent Grade 3 or 4 adverse events of peripheral neuropathy will be obtained. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Hungary |
| Israel |
| Netherlands |
| Norway |
| Poland |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end-of-study is defined as the date of the last subject's last visit, or last follow-up visit, which is longer. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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