| Eligibility |
Inclusion Criteria:
- Patients must have histologically confirmed advanced solid tumors refractory to
standard-of-care (SOC) therapy; or no SOC therapy; or declined SOC. During dose
expansion, patients have to have one of the following genetic and pathologic features
as defined in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory
as well:
- A deleterious BRCA1 or BRCA2 mutation (germline or somatic)
- A surrogate biomarker for HRD: deleterious mutation or deletion of MRE11, RAD50,
NBS1, ATM, ATR, CHEK1, CHEK2, PALB2, ARID1A, Fanconi anemia genes, and PTEN, or
loss of PTEN by IHC, amplification of EMSY, etc
- Patients in the dose-escalation phase must have evaluable and/or measurable disease as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients in the
dose expansion phase must have measurable disease per RECIST 1.1 and at least one
additional lesion that can be biopsied
- Patients age >= 18 years
- For women of child-bearing potential (women who have not been postmenopausal for at
least one year or are not surgically sterile) and all men, agreement to use highly
effective contraception (e.g., hormonal contraception, barrier device, or abstinence)
prior to study entry for the duration of study participation and for 180 days after
the last dose of the study agents. Nonsterile males must avoid sperm donation for the
duration of the study and for at least 6 months after the last dose of the study
agents
- White blood cell count >= 2,500/uL, without granulocyte colony-stimulating factor
support (within 14 days before first dose of study treatment)
- Absolute neutrophil count (ANC) >= 1,500/uL, without granulocyte colony-stimulating
factor support (within 14 days before first dose of study treatment)
- Hemoglobin >= 9 g/dL (within 14 days before first dose of study treatment)
- Platelets >= 100,000/uL, without transfusion (within 14 days before first dose of
study treatment)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (upper limit of normal), or total
bilirubin < 3.0 x ULN with direct bilirubin =< ULN in patients with well documented
Gilbert's syndrome (within 14 days before first dose of study treatment)
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (AKP) =< 3 x ULN. AKP =< 5 x ULN with documented bone metastases (within
14 days before first dose of study treatment)
- Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 45 mL/min by the
Cockcroft-Gault method (within 14 days before first dose of study treatment)
- Serum albumin >= 2.8 g/dL (within 14 days before first dose of study treatment)
- Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-h urine
protein =< 1 g (within 14 days before first dose of study treatment)
- Prothrombin time (PT)/institutional normalized ratio (INR) or partial thromboplastin
time (PTT) test < 1.3 x the laboratory ULN if not on therapeutic anticoagulation
(within 14 days before first dose of study treatment)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Ability to read and fully understand the requirements of the trial, willingness to
comply with all trial visits and assessments, and willingness and ability to sign an
Institutional Review Board (IRB)-approved written informed consent document
- No palliative radiation therapy delivered to the sole target lesions immediately
before or during the study
- Ability to take oral medications without medical history of malabsorption or other
chronic gastrointestinal disease, or other conditions that may hamper compliance
and/or absorption of the study agents
- No prior treatment with simultaneous inhibition of PARP and VEGF with or without c-MET
inhibition (patients may have prior therapy targeting only the c-MET, VEGF, or PARP
pathway). However, prior treatment with cabozantinib is not allowed
- Willing to provide an archival tissue block, or 10 formalin-fixed paraffin-embedded
(FFPE) slides
Exclusion Criteria:
- Any treatment specifically for systemic tumor control given within 3 weeks before the
initiation of the study drugs, within 2 weeks if cytotoxic agents were given weekly,
within 4 weeks if cytotoxic agents were given once every 3 to 4 weeks, within 6 weeks
for nitrosoureas or mitomycin C, within 5 half-lives for targeted agents with
half-lives and pharmacodynamic effects lasting < 5 days (a minimum of 10 days is
required), or failure to recover from toxic effects of any therapy before the
initiation of the study drugs
- Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
eligible
- Major surgery (e.g., laparoscopic nephrectomy, gastrointestinal (GI) surgery, removal
or biopsy of brain metastasis) within 4 weeks before first dose of study treatment.
Minor surgeries within 10 days before first dose of study treatment. Subjects must
have complete wound healing from major surgery or minor surgery before first dose of
study treatment. Subjects with clinically relevant ongoing complications from prior
surgery are not eligible
- Unresolved grade 1 or higher toxicity from prior therapy that is clinically
significant
- Patient has an inability to swallow oral medications. Note: Patient may not have a
percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral
nutrition (TPN)
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
treatment.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism) within 6 months before first dose of study
treatment.
- Note: Subjects with a diagnosis of incidental, subsegmental pulmonary
embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed
if stable, asymptomatic, and treated with a stable dose of permitted
anticoagulation (see exclusion criterion #6) for at least 1 week before
first dose of study treatment.
- Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
- The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
acute obstruction of the pancreatic duct or common bile duct, or gastric
outlet obstruction.
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose of study treatment.
- Note: Complete healing of an intra-abdominal abscess must be confirmed
before first dose of study treatment.
- Other clinically significant disorders that would preclude safe study
participation.
- Serious non-healing wound/ulcer/bone fracture.
- Uncompensated/symptomatic hypothyroidism.
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment
- No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer
therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy
or other novel agent is to be permitted while the patient is receiving study
medication. Patients on LHRH analogue treatment for more than 6 months are allowed
entry into the study and may continue at the discretion of the Investigator
- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
first dose of study treatment after major surgery (e.g., removal or biopsy of brain
metastasis). Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment. Leptomeningeal or lymphangitic carcinomatosis is not allowed
- Patient has had prescription or non-prescription drugs or other products known to be
moderate to strong inhibitors or inducers of CYP3A which cannot be discontinued at
least 5 half-lives if known, or 14 days if unknown prior to day 1 of dosing, and
withheld throughout the study until 2 weeks after the last dose of study drug
- Herbal preparations are not allowed throughout the study. These herbal medications
include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients
should stop using these herbal medications 5 half-lives if known or 14 days if unknown
prior to first dose of study treatment
- Any known hypersensitivity or contraindication to the components of the study drugs
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment [QTcf =
QT/(RR^0.33); RR interval = 60/heart rate], or congenital long QT syndrome.
- Note: If a single electrocardiography (ECG) shows a QTcF with an absolute value >
500 ms, two additional ECGs at intervals of approximately 3 min must be performed
within 30 min after the initial ECG, and the average of these three consecutive
results for QTcF will be used to determine eligibility
- Pregnant or breastfeeding women
- Serious active infection at the time of study entry, or another serious underlying
medical condition that would impair the ability of the patient to receive study
treatment
- Any other active malignancy at time of first dose of study treatment or diagnosis of
another malignancy within 3 years prior to first dose of study treatment that requires
active treatment, except for locally curable cancers that have been apparently cured,
such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
in situ of the prostate, cervix, or breast
- Grade 2 or higher peripheral neuropathy
- Human immunodeficiency virus requiring highly active antiretroviral therapy (HAART)
treatment due to unknown drug-drug interactions or has known active hepatitis B (e.g.,
hepatitis B surface antigen [HBsAg] reactive) or C virus (e.g., hepatitis C virus
[HCV] ribonucleic acid [RNA] [quantitative] is detected) infection: patients who have
had active hepatitis B virus [HBV] or HCV infections in the past but have evidence of
viral clearance as shown by negative viral load, i.e., undetectable HBV DNA or HCV
RNA, will be eligible
- Lesions invading or encasing any major blood vessels. Cavitating pulmonary lesion(s)
or known endotracheal or endobronchial disease manifestation
- Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
- Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH).
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor
- Vaccination with live vaccine within 4 weeks of treatment start
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