| Eligibility |
Inclusion Criteria:
Part A
1. = 18 years of age.
2. Histologically or cytologically confirmed malignancy that is metastatic or
unresectable. Subjects must have either:
1. Non-rapidly progressive disease. This means not requiring initiation of
chemotherapy (within 8 weeks), based on clinician's evaluation.
2. No effective standard of care options.
3. Subjects must have triple negative breast cancer (maximum 10% ER expression), platinum
sensitive (= 6 months since last platinum containing therapy) high grade serous
ovarian cancer or BRCA1/2 mutated (non-)breast and (non-)ovarian cancer.
4. The subject has had a maximum of 3 prior DNA damaging agents or cytotoxic chemotherapy
treatments (prior therapies with biologic agents including, IL-2, interferon,
vaccines, immunostimulating agents, immune checkpoint inhibitors and signal
transduction inhibitors are allowed and do not count as a cytotoxic chemotherapy
treatment line). Chemotherapy received as adjuvant therapy will not be considered as
prior chemotherapy when administered at least 1 year before advanced disease has been
detected.
5. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 1.
6. Adequate hematologic, renal and hepatic function as follows:
- Absolute Neutrophil Count (ANC) = 1500/µL.
- Platelet = 100,000/µL.
- Hemoglobin = 5.6 mmol/L.
- Serum creatinine = 1.5 × upper normal limit of institution's normal range OR
creatinine clearance = 50 mL/min/1.73 m2 for subjects with creatinine levels
above institutional normal.
- Bilirubin = 1.5 × the upper normal limit of institution's normal range.
- Aspartate Aminotransferase (AST) and Alanine Transaminase (ALT = 2.5 ) x the
upper normal limit of institution's normal range. For subjects with liver
metastases, AST and ALT < 5 x the upper normal limit of institution's normal
range.
- APTT must be = 1.5 × upper normal limit of institution's normal range and
International Normalized Ratio (INR) < 1.5 for subjects not on anticoagulant
therapy. Subjects on anticoagulant (such as Coumadin) will have PTT and INR as
determined by the investigator.
- Serum pregnancy test for women of childbearing potential, including women who
have had a tubal ligation; childbearing potential is defined as not having
undergone surgical sterilization, hysterectomy, and/or bilateral oophorectomy, or
not being postmenopausal (= 12 months of amenorrhea).
7. Females 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 up to 90 days following completion of therapy.
8. Measurable disease, as defined by standard RECIST v1.1 or GCIG guidelines using ca-125
in ovarian cancer. Previously irradiated lesions should not be counted as target
lesions.
9. Metastatic or locally advanced lesion(s) of which a histological biopsy can safely be
obtained according to standard clinical care procedures. Boney lesions are not
acceptable as biopsy site.
10. 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) prior to the initiation of any screening or study-specific procedures.
Part B
1. = 18 years of age.
2. Histologically or cytologically confirmed malignancy that is metastatic or
unresectable. Subjects must have either:
1. Non-rapidly progressive disease. This means not requiring initiation of
chemotherapy (within 8 weeks), based on clinician's evaluation.
2. No effective standard of care options.
3. Subjects with an intermediate risk of HR deficiency: head and neck cancer, non-small
cell lung cancer, ER+/Grade III breast cancer, gastro-intestinal cancer, bladder
cancer, ovarian cancer (not platinum sensitive high grade serous, these are eligible
for part A), prostate cancer and endometrial cancer, non-small cell lung cancer
(squamous histology only) with defective HR as assessed by the (ex-vivo) RAD51 assay.
4. The subject has received up to 3 prior DNA damaging agents or cytotoxic chemotherapy
treatments (prior therapies with biologic agents including, IL-2, interferon,
vaccines, immunostimulating agents, immune checkpoint inhibitors and signal
transduction inhibitors are allowed). Chemotherapy received as adjuvant therapy (with
an interval more than 1 year) will not be considered as prior chemotherapy.
5. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 1.
6. Adequate hematologic, renal and hepatic function as follows:
- Absolute Neutrophil Count (ANC) = 1500/µL.
- Platelet = 100,000/µL.
- Hemoglobin = 5.6 mmol/L.
- Serum creatinine = 1.5 upper normal limit of institution's normal ranger OR
creatinine clearance = 50 mL/min/1.73 m2 for subjects with creatinine levels
above institutional normal.
- Bilirubin = 1.5 × the upper normal limit of institution's normal range.
- AST and ALT = 2.5 × the upper normal limit of institution's normal range. For
subjects with liver metastases, AST and ALT < 5 × the upper normal limit of
institution's normal range.
- APTT must be = 1.5 × upper normal limit of institution's normal range and
International Normalized Ratio (INR) < 1.5. Subjects on anticoagulant (such as
Coumadin) will have PTT and INR as determined by the investigator.
- Serum pregnancy test for women of childbearing potential, including women who
have had a tubal ligation; childbearing potential is defined as not having
undergone surgical sterilization, hysterectomy, and/or bilateral oophorectomy, or
not being postmenopausal (= 12 months of amenorrhea).
7. Females 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 up to 90 days following completion of therapy.
8. Measurable disease, as defined by standard RECIST v1.1. Previously irradiated lesions
should not be counted as target lesions.
9. Metastatic or locally advanced lesion(s) of which a histological biopsy can safely be
obtained according to standard clinical care procedures.
10. 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 the initiation of any
screening or study-specific procedures.
Exclusion Criteria:
Both part A and B:
1. Received any anti-cancer therapy including chemotherapy, immunotherapy, anti-hormonal
therapy, radiotherapy, biologic or any investigational therapy within either 28 days,
or 5 half-lives of a targeted therapy (whichever is shorter), prior to the first dose
of veliparib.
- For prostate cancer, subjects receiving bisphosphonates are eligible if the
subject has been on stable doses of bisphosphonates for the 2 months prior to
study initiation without Grade 2 or greater toxicities. For breast cancer
patients bisphosphonates are allowed.
- For prostate cancer, Luteinizing Hormone Releasing Hormone (LHRH) analogue agents
are allowed if the subject has received LHRH analogues during the 2 months prior
to study initiation.
2. Has known central nervous system (CNS) metastases, unless treated properly with stable
disease (without dexamethasone or with a stable or reducing dose of dexamethason) for
at least 3 months prior to study entry.
3. Patients at high risk for seizure such as uncontrolled seizure disorder or focal or
generalized seizure within the last 12 months.
4. Clinically significant and uncontrolled major medical condition(s) including but not
limited to:
- Active uncontrolled infection.
- Subject has previous or current malignancies at other sites, with the exception
of:
- Adequately treated in situ carcinoma of the cervix uteri;
- Basal or squamous cell carcinoma of the skin;
- Previous malignancy (e.g., localized prostate cancer) confined and
surgically resected, treated with chemotherapy or radiation therapy, and is
considered cured by the investigator.
- Symptomatic congestive heart failure.
- Unstable angina pectoris or cardiac arrhythmia.
- Psychiatric illness/social situation that would limit compliance with study
requirements.
- QTc with Frederichs correction >470 ms.
- Any medical condition, which in the opinion of the study investigator places the
subject at an unacceptably high risk for toxicities.
5. Pregnant or breastfeeding female.
6. Consideration by the investigator, for any reason, that the subject is an unsuitable
candidate to receive veliparib .
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