Niraparib in Combination with Cabozantinib (XL184) in Patients with Advanced Urothelial Cancer (NICARAGUA)

Inclusion Criteria:

Phase I study:

1. Histologically confirmed UC of the urinary tract or renal cell carcinoma
2. Advanced or metastatic disease that is not amenable to curative surgery or radiation
3. Patients must be willing to provide a tumor specimen prior to enrollment
4. Previous therapy:

   i.Renal cell carcinoma: Prior tyrosine kinase inhibitor (TKI) and mechanistic target of rapamycin (mTOR) therapies is allowed ii.UC of the urinary tract: ≤2 previous chemotherapy regimens (including a platinum-based regimen)
5. Measurable disease will not be required
6. The remaining inclusion/exclusion criteria will be identical to the phase II study
7. Recovery to at least grade I from toxicities related to prior treatment unless non clinically significant or stable on supportive therapy

Phase II study:

1. Age ≥18 years
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1
3. Histologically confirmed UC of the bladder, urethra, ureter or renal pelvis (patients with mixed histologies will be allowed if urothelial is the predominant component).
4. Patients must have formalin-fixed paraffin-embedded (FFPE) tumor samples available from the primary or recurrent cancer or agree to undergo fresh biopsy prior to study treatment initiation
5. Advanced or metastatic disease that is not amenable to curative surgery or radiation
6. Prior treatment with one prior cytotoxic regimen of platinum-based chemotherapy. If the only prior cytotoxic therapy was administered in perioperative (ie, neoadjuvant or adjuvant) settings, the patient will be eligible provided the interval from end of therapy to the diagnosis of metastatic disease is less than one year.
7. Confirmed progressive disease after treatment with platinum-based chemotherapy
8. At least one measurable disease site that has not been previously irradiated
9. No prior therapy with Poly(ADP-ribose) polymerase (PARP) or c-Met inhibitors.
10. Prior anti programmed cell death protein 1 (PD1) and anti programmed death-ligand 1 (PD-L1) therapy is permitted
11. Adequate bone marrow, liver and renal functions as assessed by the following:

    * Hemoglobin ≥9 g/dL; absolute neutrophil count ≥1500 cells/µL; platelets ≥100,000 g/µL;
    * Total bilirubin ≤1.5 times upper limit of normal (ULN) (≤2.0 in patients with known Gilberts syndrome); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times ULN unless liver metastases are present, in which case they must be ≤5x ULN.
    * Serum creatinine ≤1.5x ULN or creatinine clearance ≥30 mL/min using Cockcroft-Gault formula
    * Urine protein/creatinine ratio (UPCR) ≤1 mg/mg (113.2 mg/mmol) creatinine or 24-hr urine protein of \<1 g
12. Life expectancy greater than 3 months
13. Patients must be able to take oral medications
14. Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.
15. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
16. Female participant has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential. Non-childbearing potential is defined as follows (by other than medical reasons):

    * ≥45 years of age and has not had menses for \>1 year
    * Patients who have been amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation a. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
17. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.
18. Male participant agrees to use an adequate method of contraception starting with the first dose of study treatment through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
19. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent

Exclusion Criteria:

1. Participant must not be simultaneously enrolled in any interventional clinical trial
2. Major surgery, open biopsy or significant traumatic injury within 8 weeks prior to study entry and complete wound healing at the inclusion
3. Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
4. Progressed while on platinum treatment or within 2 months from completion of platinum-containing regimen. Exclusion criteria applicable only to patients included in phase II.
5. Radiation therapy for bone or brain metastases within 4 weeks before first dose of study drug. Other external radiation within 4 weeks before first dose of study drug. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
6. Participant must not have a known hypersensitivity to niraparib or cabozantinib components or excipients.
7. Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
8. Participant must not have received colony stimulating factors (eg, granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
9. Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted \> 4 weeks and was related to the most recent treatment.
10. Known history of myelodysplastic syndrome (MDS) or a pre-treatment cytogenetic testing result at risk for a diagnosis of MDS/acute myeloid leukemia (AML)
11. Unstable systemic disease or active uncontrolled infection
12. Any concurrent active malignancy requiring treatment (other than basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or malignancies curatively treated \> 3 years prior to study entry)
13. Known uncontrolled symptomatic brain or leptomeningeal metastases or cranial epidural disease; subjects with brain metastases previously treated and on stable dose of corticosteroids and/or anticonvulsants for \>4 weeks, or not requiring such medications, are eligible. Baseline brain scans are not required to confirm eligibility.
14. Uncontrolled hypertension
15. Significant cardiovascular diseases, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomization, congestive heart failure \> New York Heart Association (NYHA) III, severe peripheral vascular disease, QT prolongation \>470 msec ,clinically significant pericardial effusion
16. Receiving concomitant medications that prolong corrected QT and is unable to discontinue use
17. Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 100 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
18. Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test ≥1.3 x ULN within 7 days before the first dose of study treatment
19. Significant thromboembolic or vascular disorders within 6 months prior to administration of study drugs, including:

    * Symptomatic pulmonary embolism
    * Cerebrovascular accident
    * Peripheral arterial ischemia \> grade 2
    * Coronary or peripheral artery bypass graft
20. The subject has experienced any of the following within 3 months before the first dose of study treatment:

    * clinically significant hematemesis or gastrointestinal bleeding
    * clinically significant hemoptysis
21. Any malabsorption problem that, in the investigator's opinion, would prevent adequate absorption of the study drug
22. Patient has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant Adverse Events
23. History of organ transplant
24. Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
25. Active infection requiring systemic treatment within 28 days before the first dose of study treatment
26. Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
27. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

    * Any of the following within 28 days before the first dose of study treatment: intra-abdominal tumor/metastases invading gastrointestinal mucosa, active peptic ulcer disease,inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    * Any of the following within 6 months before the first dose of study treatment: History of abdominal fistula, gastrointestinal perforation, bowel obstruction or gastric outlet obstruction or intra-abdominal abscess
28. Chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort)