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Trial record 18 of 93 for:    cabozantinib

Niraparib in Combination With Cabozantinib (XL184) in Patients With Advanced Urothelial Cancer

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ClinicalTrials.gov Identifier: NCT03425201
Recruitment Status : Not yet recruiting
First Posted : February 7, 2018
Last Update Posted : March 16, 2018
Sponsor:
Collaborators:
Ipsen
Tesaro, Inc.
Information provided by (Responsible Party):
Fundacion CRIS de Investigación para Vencer el Cáncer

Brief Summary:

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor. Its primary targets are Hepatocyte growth factor receptor protein (MET), vascular endothelial growth factor receptor 1-3 (VEGFR1-3), RET, AXL, FLT3 and KIT. Cabozantinib has been approved by the FDA for clinical treatment of progressive, metastatic medullary thyroid cancer. Recently published trials have demonstrated activity for cabozantinib in patients with advanced renal cell carcinoma and metastatic castration-resistant prostate cancer (mCRPC). Furthermore, in preclinical models of urothelial carcinoma (UC) of the bladder, cabozantinib has demonstrated the ability to inhibit tumor xenograft growth. It has been suggested that levels of soluble Met ectodomain (sMet) can be measured in the urine as a useful biomarker to monitor the efficacy of c-Met therapy in bladder cancer patients. Moreover, cabozantinib has demonstrated activity in heavily pretreated, advanced bladder cancer patients, with a response rate of 19.5% and manageable toxicities.

In the phase I of this study it is proposed to evaluate DLTs of niraparib and cabozantinib combination and determine maximum tolerated dose (MTD) in patients with advanced urothelial or renal cell carcinoma. In the phase II it is proposed to make a preliminary evaluation of the efficacy of this combination in patients with urothelial cell carcinoma. Efficacy results will be correlated with genomic alterations related to c-Met and Poly [ADP-ribose] polymerase (PARP) inhibitor activity.


Condition or disease Intervention/treatment Phase
Urothelial Cancer Drug: Niraparib plus Cabozantinib Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, multicenter, phase I/II dose-escalation study
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase I-II Study to Evaluate the Efficacy and Safety of Niraparib in Combination With Cabozantinib (XL184) in Patients With Advanced Urothelial Cancer After Failure to First-line Platinum-based Chemotherapy
Estimated Study Start Date : September 2018
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Niraparib plus Cabozantinib

Patients will receive niraparib and cabozantinib p.o. once daily in 28-day cycles.

In phase I, patients will be accrued to each dose level in cohorts of 6 patients. Escalation will continue until a dose-limiting toxicity (DLT) is observed or the highest dose-level is reached.

In phase II study patients will receive niraparib p.o. once daily and cabozantinib p.o. once daily in 28-day cycles at doses recommended in the phase I study.

Drug: Niraparib plus Cabozantinib
Non-randomized trial will comprise 2 stages. A dose escalation phase will characterize the safety, tolerability, DLTs and MTD, of oral niraparib plus cabozantinib in patients with urothelial or renal cell carcinoma. Subsequently, the phase II will further evaluate the safety and antitumor activity of this combination in patients with urothelial carcinoma.



Primary Outcome Measures :
  1. Phase I: maximum tolerated dose [ Time Frame: up to 1 month ]
    Highest dose at which ≤1 out of 6 patients experience a DLT

  2. Phase II: progression free survival [ Time Frame: Up to 6 months ]
    Time from the date of first dose of study treatment to the date of progression or death (from any cause).


Secondary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: Up to 6 months ]
    Number of events per patient

  2. Phase II: Objective Response Rate [ Time Frame: Up to 6 months ]
    Response according to RECIST 1.1 criteria

  3. Phase II: Disease Control Rate [ Time Frame: Up to 6 months ]
    Response according to RECIST 1.1 criteria

  4. Phase II: Duration of response [ Time Frame: Up to 6 months ]
    Time from the date of response is achieved until documented tumor progression

  5. Phase II: Overall Survival [ Time Frame: Up to 6 months ]
    Time from the date of first dose of study treatment to the date of death due to any cause


Other Outcome Measures:
  1. Correlation of the activity of niraparib plus cabozantinib with the molecular profile of the tumor [ Time Frame: Up to 6 months ]
    Immunohistochemistry and RNA analysis of pre- and post-tumor samples



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03425201


Contacts
Contact: Ana Moreno, MD +34918166804 ana.moreno@apices.es

Locations
Spain
ICO Badalona
Badalona, Spain
Hospital Clinic
Barcelona, Spain
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain
ICO L'Hospitalet
L'Hospitalet De Llobregat, Spain
ICO L'Hospitalet Not yet recruiting
L'Hospitalet De Llobregat, Spain
Contact: Nuria Sala         
Hospital 12 de Octubre
Madrid, Spain
Althaia Xarxa Not yet recruiting
Manresa, Spain
Contact: Montserrat Domenech         
Instituto Valenciano de Oncología
Valencia, Spain
Sponsors and Collaborators
Fundacion CRIS de Investigación para Vencer el Cáncer
Ipsen
Tesaro, Inc.
Investigators
Principal Investigator: Albert Font, MD ICO Badalona-Hospital Germans Trias i Pujol
Principal Investigator: Daniel Castellano, MD Hospital 12 de Octubre

Responsible Party: Fundacion CRIS de Investigación para Vencer el Cáncer
ClinicalTrials.gov Identifier: NCT03425201     History of Changes
Other Study ID Numbers: NICARAGUA
First Posted: February 7, 2018    Key Record Dates
Last Update Posted: March 16, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents