Clinical Trials /

Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors

NCT02496208

Description:

This phase I trial studies the side effects and best doses of cabozantinib s-malate and nivolumab with or without ipilimumab in treating patients with genitourinary (genital and urinary organ) tumors that have spread to other places in the body (metastatic). Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving cabozantinib s-malate and nivolumab alone or with ipilimumab works better in treating patients with genitourinary tumors.

Related Conditions:
  • Bladder Adenocarcinoma
  • Bladder Carcinoma
  • Bladder Small Cell Neuroendocrine Carcinoma
  • Bladder Squamous Cell Carcinoma
  • Cervical Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Extragonadal Embryonal Carcinoma
  • Kidney Medullary Carcinoma
  • Malignant Bladder Neoplasm
  • Malignant Ovarian Germ Cell Tumor
  • Malignant Renal Pelvis Neoplasm
  • Malignant Reproductive System Neoplasm
  • Malignant Ureter Neoplasm
  • Malignant Urethral Neoplasm
  • Ovarian Embryonal Carcinoma
  • Renal Pelvis Carcinoma
  • Renal Pelvis and Ureter Carcinoma
  • Squamous Cell Carcinoma of the Penis
  • Testicular Embryonal Carcinoma
  • Transitional Cell Carcinoma
  • Ureter Carcinoma
  • Ureter Small Cell Carcinoma
  • Urethral Carcinoma
  • Urothelial Carcinoma
  • Uterine Corpus Neuroendocrine Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors
  • Official Title: A Phase 1 Study of Cabozantinib Plus Nivolumab (CaboNivo) Alone or in Combination With Ipilimumab (CaboNivoIpi) in Patients With Advanced/Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-02379
  • SECONDARY ID: NCI-2014-02379
  • SECONDARY ID: 15-C-0160
  • SECONDARY ID: P141706
  • SECONDARY ID: 150160
  • SECONDARY ID: 9681
  • SECONDARY ID: 9681
  • SECONDARY ID: UM1CA186712
  • SECONDARY ID: UM1CA186716
  • SECONDARY ID: UM1CA186717
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT02496208

Conditions

  • Bladder Small Cell Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant
  • Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
  • Kidney Medullary Carcinoma
  • Metastatic Malignant Neoplasm in the Bone
  • Metastatic Penile Carcinoma
  • Metastatic Renal Cell Carcinoma
  • Progressive Disease
  • Renal Pelvis Urothelial Carcinoma
  • Sarcomatoid Renal Cell Carcinoma
  • Squamous Cell Carcinoma of the Penis
  • Stage III Bladder Adenocarcinoma AJCC v6 and v7
  • Stage III Bladder Squamous Cell Carcinoma AJCC v6 and v7
  • Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
  • Stage III Penile Cancer AJCC v7
  • Stage III Renal Cell Cancer AJCC v7
  • Stage III Renal Pelvis Cancer AJCC v7
  • Stage III Ureter Cancer AJCC v7
  • Stage III Urethral Cancer AJCC v7
  • Stage IIIa Penile Cancer AJCC v7
  • Stage IIIb Penile Cancer AJCC v7
  • Stage IV Bladder Adenocarcinoma AJCC v7
  • Stage IV Bladder Squamous Cell Carcinoma AJCC v7
  • Stage IV Bladder Urothelial Carcinoma AJCC v7
  • Stage IV Penile Cancer AJCC v7
  • Stage IV Renal Cell Cancer AJCC v7
  • Stage IV Renal Pelvis Cancer AJCC v7
  • Stage IV Ureter Cancer AJCC v7
  • Stage IV Urethral Cancer AJCC v7
  • Ureter Urothelial Carcinoma
  • Urethral Urothelial Carcinoma

Interventions

DrugSynonymsArms
CabozantinibPart I (cabozantinib s-malate, nivolumab)
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Part I (cabozantinib s-malate, nivolumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyPart II (cabozantinib s-malate, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoPart I (cabozantinib s-malate, nivolumab)

Purpose

This phase I trial studies the side effects and best doses of cabozantinib s-malate and nivolumab with or without ipilimumab in treating patients with genitourinary (genital and urinary organ) tumors that have spread to other places in the body. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving cabozantinib s-malate and nivolumab alone or with ipilimumab works better in treating patients with genitourinary tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of the
      combination of cabozantinib (cabozantinib s-malate) and nivolumab (cabo-nivo) and separately
      the combination of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with
      genitourinary tumors. (Phase I) II. Assess safety and tolerability of cabozantinib, nivolumab
      and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors at this novel dose.
      (Dose Level 8 Cohort)

      SECONDARY OBJECTIVES:

      I. Preliminarily evaluate the activity, as determined by objective response rate using
      Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the modified Immune-Related
      Response Criteria (irRC), derived from RECIST1.1, of Ia. Cabo-nivo and cabo-nivo-ipi in
      patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition
      therapy naive) and with renal cell carcinoma in the second-line and beyond setting.

      Ib. Cabo-nivo in patients with adenocarcinoma and with rare histologies (including squamous
      or small cell carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and
      renal cell carcinomas, plasmacytoid carcinoma of the bladder and others) in the first line or
      beyond setting.

      Ic. Cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint
      inhibition therapy in the second line or beyond setting.

      Id. Cabo-nivo-ipi in patients with squamous cell carcinoma of the penis.

      II. To evaluate the activity as determined by progression free survival (PFS) and overall
      survival (OS) of:

      IIa. Cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial
      carcinoma (checkpoint inhibition therapy naïve) or with renal cell carcinoma in the
      second-line and beyond setting.

      IIb. Cabo-nivo in patients with adenocarcinoma and with rare histologies (including squamous,
      small cell carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and
      renal cell carcinomas, plasmacytoid carcinoma of the bladder and others) in the first line or
      beyond setting.

      IIc. Cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint
      inhibition therapy in the second line or beyond setting.

      IId. Cabo-nivo-ipi in patients with squamous cell carcinoma of the penis. III. To obtain
      additional data to evaluate the safety of both combinations in patients with clear cell renal
      cell carcinoma (ccRCC).

      IV. To assess the number of malignant soft tissue and bone lesions on fludeoxyglucose F-18
      (18F-FDG) positron emission tomography (PET)/computed tomography (CT) (scan 1) versus
      combined fluorine F 18 sodium fluoride (18F-NaF) and 18F-FDG PET/CT (scan 2).

      V. To assess response assessment by RECIST 1.1 using CT of the chest, abdomen, and pelvis
      with intravenous (IV) contrast versus assessment by combined 18F-NaF and 18F-FDG PET/CT (scan
      2) using number of malignant and change (modified PET RECIST [PERCIST]) of soft tissue and
      bone lesions.

      VI. To assess PDL-1 and MET expression data and in exploratory fashion analyze their
      association to response or clinical benefit.

      EXPLORATORY OBJECTIVES:

      I. To assess overall response rates (ORR) on patients who have been challenged or
      re-challenged with ipilimumab therapy post disease progression.

      II. To assess effects of treatment in patients with bone-only disease.

      OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment arms.

      PART I: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and
      nivolumab intravenously (IV) over 30 minutes on days 1 and 15. Cycles repeat every 28 days in
      the absence of disease progression or unacceptable toxicity. After 21 cycles, patients
      receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or
      unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO,
      nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib
      s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of
      disease progression or unacceptable toxicity.

      PART II: Patients receive cabozantinib s-malate PO QD on days 1-21, nivolumab IV over 30
      minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days
      for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After
      completion of 4 cycles with ipilimumab, patients continue receiving cabozantinib s-malate PO
      QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28
      days for up to 21 cycles in the absence of disease progression or unacceptable toxicity.
      After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence
      of disease progression or unacceptable toxicity. After progression, patients may receive
      cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles
      followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if
      post-cycle 21 in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 16 weeks, and then every 1-3
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Part I (cabozantinib s-malate, nivolumab)ExperimentalPatients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate
  • Nivolumab
Part II (cabozantinib s-malate, nivolumab, ipilimumab)ExperimentalPatients receive cabozantinib s-malate PO QD on days 1-21, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of 4 cycles with ipilimumab, patients continue receiving cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 21 cycles in the absence of disease progression or unacceptable toxicity. After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients in the phase I portion must have:

               -  Histologically confirmed diagnosis of metastatic, genitourinary solid tumor

               -  Metastatic disease defined as new or progressive lesions on cross-sectional
                  imaging; patients must have at least:

                    -  One evaluable site of disease

                    -  Or, appearance of one new bone lesion

          -  Patients in the expansion portion must have:

               -  Histologically confirmed diagnosis of metastatic:

                    -  Urothelial carcinoma of the bladder, urethra, ureter, renal pelvis, OR

                    -  Clear cell renal cell carcinoma OR

                    -  Adenocarcinoma of the bladder OR

                    -  Non-resectable squamous cell carcinoma of the penis OR

                    -  Squamous or small cell carcinoma of the bladder, renal medullary carcinoma
                       (RMC), sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma
                       of the bladder or other rare bladder/kidney cancer histology AND

               -  Patients with urothelial cancer or renal cell carcinoma must have progressive
                  metastatic disease defined as new or progressive lesions on cross-sectional
                  imaging; patients must have at least:

                    -  One measurable site of disease (according to RECIST criteria) or bone
                       disease by NaF PET/CT

          -  Patients must have either progressed on least one standard therapy or there must be no
             standard treatment that has been shown to prolong survival for the patient's disease
             (patients with urothelial carcinoma who are cisplatin-ineligible may receive protocol
             therapy as a first line therapy); patients may have received any number of prior
             cytotoxic agents

          -  Karnofsky performance status >= 70%

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,200/mcL

          -  Platelets >= 75,000/mcL

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN); for subjects with known
             Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total
             bilirubin =< 3.0 mg/dL

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3.0 x institutional upper limit of normal (ULN)

          -  Creatinine =< 1.5 x ULN OR creatinine clearance >= 40 mL/min/1.73 m^2 (calculated
             using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] equation or
             Cockcroft-Gault formula) for patients with creatinine levels above institutional
             normal

          -  Hemoglobin >= 9 g/dL

          -  Serum albumin >= 2.8 g/dL

          -  Lipase and amylase =< 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

          -  Urine protein/creatinine ratio (UPCR) =< 2

          -  Serum phosphorus >= lower limit of normal (LLN) (if below LLN, for asymptomatic
             patients replacement may be initiated if clinically indicated without delaying the
             start of study treatment)

          -  Serum calcium >= LLN (if below LLN, for asymptomatic patients replacement may be
             initiated if clinically indicated without delaying the start of study treatment)

          -  Serum magnesium >= LLN (if below LLN, for asymptomatic patients replacement may be
             initiated if clinically indicated without delaying the start of study treatment)

          -  Serum potassium >= LLN (if below LLN, for asymptomatic patients replacement may be
             initiated if clinically indicated without delaying the start of study treatment)

          -  Women of childbearing potential must have a negative pregnancy test at screening;
             women of childbearing potential include women who have experienced menarche and who
             have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is
             defined as amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic
             for 12 or more months are still considered to be of childbearing potential if the
             amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression
             or any other reversible reason

          -  The effects of the drugs used in this trial on the developing human fetus are unknown;
             however, cabozantinib was embryolethal in rats at exposures below the 140mg dose in
             the label, with increased incidences of skeletal variations in rats and visceral
             variations and malformations in rabbits; for this reason and because tyrosine kinase
             inhibitors agents as well as other therapeutic agents used in this trial are known to
             be teratogenic, women of child-bearing potential and men must agree to use adequate
             contraception, as defined below, prior to study entry and for the duration of study
             participation; should a woman become pregnant or suspect she is pregnant while she is
             participating in this study, she should inform her treating physician immediately; men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 7 months after
             completion of all study medications; women treated or enrolled on this protocol must
             also agree to use adequate contraception prior to the study, for the duration of study
             participation, and for 5 months after completion of all study medications

          -  Sexually active subjects (men and women) must agree to use medically accepted barrier
             methods of contraception (e.g., male or female condom) during the course of the study
             and for 5 or 7 months for women or men respectively, after the last dose of study
             drugs, even if oral contraceptives are also used; all subjects of reproductive
             potential must agree to use both a barrier method and a second method of birth control
             during the course of the study and for 5 or 7 months for women and men respectively
             after the last dose of study drugs

          -  Tissue availability for programmed cell death ligand 1 (PD-L1) expression is mandatory
             for enrollment; however if archived tissue is unavailable the patient will be given
             the option to consent to pre and post treatment tissue biopsies; tissue biopsies will
             be collected pretreatment (prior to the first dose of therapy) and post treatment
             (after at least 1 dose, preferably 2 doses of nivolumab)

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  The subject has received cytotoxic chemotherapy (including investigational cytotoxic
             chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or
             nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment

          -  Patients who have been previously treated with MET or vascular endothelial growth
             factor receptor (VEGFR) inhibitors (except for patients on renal cell cancer [RCC]
             cohort) are not eligible for the expansion cohorts but can enroll in the phase I
             portion

          -  Prior treatment with any therapy on the programmed cell death 1 (PD-1)/PD-L1 axis or
             anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors unless enrolling
             the urothelial carcinoma with previous checkpoint inhibition therapy expansion cohort

          -  The subject has received radiation therapy:

               -  To the thoracic cavity or abdomen within 3 months before the first dose of study
                  treatment, or has ongoing complications, or is without complete recovery and
                  healing from prior radiation therapy

               -  To bone or brain metastasis within 3 weeks before the first dose of study
                  treatment

               -  To any other site(s) within 28 days before the first dose of study treatment

          -  The subject has received radionuclide treatment within 6 weeks of the first dose of
             study treatment

          -  The subject has received prior treatment with a small molecule kinase inhibitor within
             14 days or five half-lives of the compound or active metabolites, whichever is longer,
             before the first dose of study treatment

          -  The subject has received prior treatment with hormonal therapy within 14 days or five
             half-lives of the compound or active metabolites, whichever is longer, before the
             first dose of study treatment; subjects receiving gonadotropin-releasing hormone
             (GnRH) agonists and antagonists are allowed to participate

          -  The subject has received any other type of investigational agent within 28 days before
             the first dose of study treatment

          -  The subject has not recovered to baseline or Common Terminology Criteria for Adverse
             Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and
             other non-clinically significant adverse events (AEs) defined as lab elevation with no
             associated symptoms or sequelae

          -  The subject has active brain metastases or epidural disease; subjects with brain
             metastases previously treated with whole brain radiation or radiosurgery or subjects
             with epidural disease previously treated with radiation or surgery who are
             asymptomatic and do not require steroid treatment for at least 2 weeks before starting
             study treatment are eligible; neurosurgical resection of brain metastases or brain
             biopsy is permitted if completed at least 3 months before starting study treatment;
             baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI)
             scans for subjects with known brain metastases is required to confirm eligibility

          -  The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
             thromboplastin time (PTT) test >= 1.5 x the laboratory ULN within 7 days before the
             first dose of study treatment

          -  The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
             such as warfarin or warfarin-related agents, thrombin or factor Xa inhibitors; aspirin
             (up to 325 mg/day), low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low
             molecular weight heparin (LMWH) are permitted

          -  The subject requires 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)

          -  The subject has experienced any of the following:

               -  Clinically-significant gastrointestinal bleeding within 6 months before the first
                  dose of study treatment

               -  Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the
                  first dose of study treatment

               -  Any other signs indicative of pulmonary hemorrhage within 3 months before the
                  first dose of study treatment

          -  The subject has tumor invading any major blood vessels

          -  The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus,
             stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or
             endobronchial tumor within 28 days before the first dose of cabozantinib

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

          -  Cardiovascular disorders including:

               -  Congestive heart failure (CHF): New York Heart Association (NYHA) class III
                  (moderate) or class IV (severe) at the time of screening

               -  Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) >
                  140 mmHg systolic, or > 90 mmHg diastolic despite optimal antihypertensive
                  treatment within 7 days of the first dose of study treatment

               -  The subject has a corrected QT interval calculated by the Fridericia formula
                  (QTcF) > 500 ms within 28 days before randomization; Note: if initial QTcF is
                  found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at
                  least 3 minutes should be performed; if the average of these three consecutive
                  results for QTcF is =< 500 ms, the subject meets eligibility in this regard

               -  Any history of congenital long QT syndrome

               -  Any of the following within 6 months before the first dose of study treatment:

                    -  Unstable angina pectoris

                    -  Clinically-significant cardiac arrhythmias

                    -  Stroke (including transient ischemic attack [TIA], or other ischemic event)

                    -  Myocardial infarction

                    -  Cardiomyopathy

          -  Gastrointestinal disorders particularly those associated with a high risk of
             perforation or fistula formation including:

               -  Any of the following that have not resolved within 28 days before the first dose
                  of study treatment

                    -  Intra-abdominal tumor/metastases invading GI mucosa

                    -  Active peptic ulcer disease, diverticulitis, cholecystitis, symptomatic
                       cholangitis or appendicitis

                    -  Malabsorption syndrome

               -  Any of the following within 6 months before the first dose of study treatment:

                    -  Abdominal fistula

                    -  Gastrointestinal perforation

                    -  Bowel obstruction or gastric outlet obstruction

                    -  Intra-abdominal abscess; Note: complete resolution of an intra-abdominal
                       abscess must be confirmed prior to initiating treatment with cabozantinib
                       even if the abscess occurred more than 6 months before the first dose of
                       study treatment

          -  Other disorders associated with a high risk of fistula formation including
             percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the
             first dose of study therapy

          -  Other clinically significant disorders such as:

               -  Severe active infection requiring systemic treatment within 14 days before the
                  first dose of study treatment

               -  Serious non-healing wound/ulcer/bone fracture within 28 days before the first
                  dose of study treatment

               -  History of organ transplant

               -  Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
                  before the first dose of study treatment (for asymptomatic patients with an
                  elevated thyroid stimulating hormone [TSH], thyroid replacement may be initiated
                  if clinically indicated without delaying the start of study treatment)

               -  History of major surgery as follows:

                    -  Major surgery within 3 months of the first dose of cabozantinib; however, if
                       there were no wound healing complications, patients with rapidly growing
                       aggressive cancers, may start as soon as 6 weeks if wound has completely
                       healed post-surgery

                    -  Minor surgery within 1 month of the first dose of cabozantinib if there were
                       no wound healing complications or within 3 months of the first dose of
                       cabozantinib if there were wound complications excluding core biopsies and
                       Mediport placement

               -  In addition, complete wound healing from prior surgery must be confirmed at least
                  28 days before the first dose of cabozantinib irrespective of the time from
                  surgery

          -  The subject is unable to swallow tablets

          -  History of severe hypersensitivity reaction to any monoclonal antibody

          -  The subject is unable or unwilling to abide by the study protocol or cooperate fully
             with the investigator or designee

          -  For disease specific studies: the subject has had evidence within 2 years of the start
             of study treatment of another malignancy which required systemic treatment

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cabozantinib, nivolumab, ipilimumab or other agents used in study

          -  Pregnant women are excluded from this study because cabozantinib is a tyrosine kinase
             inhibitor with the potential for teratogenic or abortifacient effects; because there
             is an unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with cabozantinib, breast
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose (Phase I)
Time Frame:Up to 4-6 weeks
Safety Issue:
Description:Will be defined as the highest dose for which no more than 1/6 patients experience a dose limiting toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safe dose level of cabozantinib and nivolumab, as well as of cabozantinib, nivolumab, and ipilimumab will be established.

Secondary Outcome Measures

Measure:Clinical response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1 and Immune-Related Response Criteria. The response rate may be used to guide the further development of the combinations.
Measure:Fraction of patients who have been identified as being alive and progression free at two months
Time Frame:At 2 months
Safety Issue:
Description:May be determined as well and reported on both arms. This fraction will be considered as a secondary endpoint for the expansion cohorts as well, and this information may be used to guide the further development of the combinations. A Kaplan-Meier curve for progression free survival will also be presented as a secondary endpoint, in addition to reporting the fraction without progression at two months.
Measure:PDL-1 and MET expression
Time Frame:Up to day 1 of final course
Safety Issue:
Description:PDL-1 and MET expression data will be obtained in patients with urothelial carcinoma checkpoint inhibition naive, clear cell renal cell carcinoma, adenocarcinoma of the bladder, squamous cell carcinoma of the bladder, urothelial carcinoma with prior checkpoint inhibition therapy, and penile cancer. Data will be obtained in pre- and post-treatment biopsies and analyze, in at least an exploratory fashion, their association to response or clinical benefit.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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