Cabozantinib in Combination With Nivolumab and Ipilimumab in Rare Genitourinary Tumors

• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase II trial studies how well the combination of cabozantinib, nivolumab, and ipilimumab work in treating patients with rare genitourinary (GU) tumors that have spread to other places in the body. Cabozantinib 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. Giving combination of cabozantinib, nivolumab, and ipilimumab may work better in treating patients with genitourinary tumors that have no treatment options compared to giving cabozantinib, nivolumab, or ipilimumab alone.

Condition or disease	Intervention/treatment	Phase
Bladder Adenocarcinoma; Bladder Mixed Adenocarcinoma; Bladder Small Cell Carcinoma; Bladder Squamous Cell Carcinoma; Chromophobe Renal Cell Carcinoma; Infiltrating Bladder Lymphoepithelioma-Like Carcinoma; Infiltrating Bladder Urothelial Carcinoma; Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant; Infiltrating Bladder Urothelial Carcinoma With Giant Cells; Infiltrating Bladder Urothelial Carcinoma, Nested Variant; Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant; Kidney Medullary Carcinoma; Large Cell Neuroendocrine Carcinoma; Metastatic Bladder Carcinoma; Metastatic Bladder Large Cell Neuroendocrine Carcinoma; Metastatic Bladder Small Cell Neuroendocrine Carcinoma; Metastatic Bladder Squamous Cell Carcinoma; Metastatic Infiltrating Bladder Urothelial Carcinoma, Lipid-Cell Variant; Metastatic Kidney Medullary Carcinoma; Metastatic Malignant Genitourinary System Neoplasm; Metastatic Penile Carcinoma; Metastatic Plasmacytoid Urothelial Carcinoma; Metastatic Prostate Small Cell Carcinoma; Metastatic Sarcomatoid Renal Cell Carcinoma; Metastatic Sarcomatoid Urothelial Carcinoma; Papillary Renal Cell Carcinoma; Sarcomatoid Renal Cell Carcinoma; Stage IV Bladder Cancer AJCC v8; Stage IV Penile Cancer AJCC v8; Stage IV Prostate Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Stage IVA Bladder Cancer AJCC v8; Stage IVA Prostate Cancer AJCC v8; Stage IVB Bladder Cancer AJCC v8; Stage IVB Prostate Cancer AJCC v8; Testicular Leydig Cell Tumor; Testicular Sertoli Cell Tumor	Drug: Cabozantinib; Drug: Cabozantinib S-malate; Biological: Ipilimumab; Biological: Nivolumab	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of cabozantinib s-malate (cabozantinib) combined with nivolumab and ipilimumab in the first or second-line (and beyond) setting for patients within each of the rare genitourinary (GU) variant histology group of interest, as measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.

II. To estimate the overall survival (OS) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.

III. To estimate the clinical benefit rate (defined as complete response [CR] or partial response [PR] or stable disease [SD]) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.

IV. To assess the safety of treating patients with rare variant histologies with cabozantinib combined with nivolumab and ipilimumab.

V. To support tissue banking and collection of clinical follow-up data for GU tract rare histological variants.

EXPLORATORY OBJECTIVES:

I. To assess effects of treatment in patients with bone-only disease by bone scan.

OUTLINE:

Patients receive cabozantinib orally (PO), once daily (QD) on days 1-21 of cycles 1-4, nivolumab intravenously (IV) over 30 minutes on day 1 of cycles 1-13 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. This triple combination therapy is followed by double therapy with cabozantinib PO, QD on days 1-28 and nivolumab IV over 30 minutes on day 1 of each 28 day cycle for the remaining cycles.1 Cycles repeat every 21 days for cycles 1-4 and every 28 days for subsequent cycles for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 5 years.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	330 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Rare Genitourinary Tumors
Actual Study Start Date :	April 12, 2019
Estimated Primary Completion Date :	October 1, 2021
Estimated Study Completion Date :	October 1, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (cabozantinib s-malate, nivolumab, ipilimumab); Patients receive cabozantinib PO, QD on days 1-21 of cycles 1-4, nivolumab IV over 30 minutes on day 1 of cycles 1-13 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. This triple combination therapy is followed by double therapy with cabozantinib PO, QD on days 1-28 and nivolumab IV over 30 minutes on day 1 of each 28 day cycle for the remaining cycles.1 Cycles repeat every 21 days for cycles 1-4 and every 28 days for subsequent cycles for 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Cabozantinib; Given PO; Drug: Cabozantinib S-malate; Given PO; Other Names: BMS-907351; Cabometyx; Cometriq; XL184; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: Up to 5 years ]
   An objective response is defined as a confirmed complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A confirmed tumor response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Will be estimated by the number of confirmed objective responses divided by the total number of evaluable patients. Confidence intervals for the true ORR will be calculated.

Secondary Outcome Measures :

1. Duration of response [ Time Frame: From time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years ]
   Defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented.
2. Progression-free survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 5 years ]
   The median its 95% confidence interval will be determined and will be summarized using the Kaplan-Meier estimator.
3. Overall survival [ Time Frame: Up to 5 years ]
   The median its 95% confidence interval will be determined and will be summarized using the Kaplan-Meier estimator.
4. Clinical benefit rate (CBR) [ Time Frame: Up to 5 years ]
   A confirmed clinical benefit is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart or a confirmed stable disease at two consecutive tumor assessments at least 3 months apart. The CBR will be estimated by the number of patients with confirmed clinical benefit divided by the total number of evaluable patients. Confidence intervals for the true CBR will be calculated using exact binomial confidence intervals.
5. Incidence of adverse events (AE) [ Time Frame: Up to 5 years ]
   Will be assessed using Common Terminology Criteria for Adverse Events version 5.0. The maximum of a particular AE will be determined for each patient. Tables will summarize the number and relative frequency of patients observing an AE as well as the number and relative frequency of patients experiencing any AE of grade 3 or greater.

Other Outcome Measures:

1. Effects of treatment in patients with bone-only disease [ Time Frame: Up to 5 years ]
   The bone-only tumor patients will be evaluated in an exploratory fashion (if no RECIST measurements are available). A maximum of 15 patients with bone-only disease will be enrolled and evaluated using PFS for a descriptive analysis of the effect of treatment.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Metastatic disease defined as new or progressive lesions on cross-sectional imaging. Patients must have at least:

  • One measurable site of disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
  • Histologically confirmed diagnosis of metastatic: small cell carcinoma of the bladder; adenocarcinoma of the bladder; squamous cell carcinoma of the bladder; plasmacytoid urothelial carcinoma; any penile cancer; sarcomatoid renal cell carcinoma; sarcomatoid urothelial carcinoma; renal medullary carcinoma or other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to micropapillary, giant cell, lipid-rich, clear cell and nested variants, large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer, testicular Sertoli or Leydig cell tumors, and papillary and chromophobe renal cell carcinoma (RCC)
  • 2 hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective central pathology review
• Patients may have received any number of prior anti-cancer treatments or be treatment naive (with the exception of patients with small cell carcinoma of the bladder, whom should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment)
• Patients must be able to swallow oral formulation of the tablets
• Karnofsky performance status >= 70%
• Absolute neutrophil count (ANC) >= 1,200/mcL
• Platelet count >= 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)/alanine aminotransferase (ALT) =< 3.0 x institutional upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastases or Gilbert's disease)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology [CKD-EPI] equation or Cockcroft-Gault formula) for patients with creatinine levels above institutional normal
• Hemoglobin >= 9 g/dL (transfusion of packed red blood cells [PRBCs] allowed)
• Serum albumin >= 2.8 g/dL
• Lipase and amylase =< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or clinical evidence of pancreatitis
• Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed
• Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4 inhibitors is allowed, either in the perioperative or in the metastatic setting. However, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are not allowed
• Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART), no clinically significant drug-drug interactions are anticipated with the current HAART regimen, CD4 counts are greater than 350 and viral load is undetectable
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication only and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc. are eligible but should be considered for rheumatologic evaluation for the presence of target organ involvement and potential need for systemic treatment
• Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones or medications (e.g. thyroiditis managed with propylthiouracil [PTU] or methimazole) including physiologic oral corticosteroids are eligible
• Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, and gastrointestinal (GI) obstruction, within 12 months are not eligible

• 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. Post menopause 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
• Pregnant women may not participate in this study because with cabozantinib, nivolumab, and ipilimumab have 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, nivolumab, and ipilimumab, breastfeeding should be discontinued if the mother is treated with these agents
• The patient has received no cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2 weeks before the first dose of study treatment

• The patient has received no radiation therapy:

  • To the lungs and mediastinum or abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy
  • To brain metastasis within 3 weeks for whole-brain radiotherapy (WBXRT), and 2 weeks for stereotactic body radiation therapy (SBRT) before the first dose of study treatment
  • To any other site(s) within 2 weeks before the first dose of study treatment
• The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment
• The patient has received no 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 patient has received no 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 patient has not received any other type of investigational agent within 14 days before the first dose of study treatment
• The patient must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia, neuropathy and other non-clinically significant adverse events (AEs) defined as lab elevation with no associated symptoms or sequelae
• The patient may not have active brain metastases or epidural disease. Patients 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 computed tomography (CT) or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility
• No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor Xa inhibitors, low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted

• No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) or strong CYP3A4 inhibitors

  • Because the lists of these agents are constantly changing, it is important to regularly consult medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

• The patient has not 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 per day within 1 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 patient has no tumor invading any major blood vessels
• The patient has no evidence of tumor invading the 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 patient has no 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) > 150 mm Hg systolic, or > 90 mm Hg 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 registration of study treatment:

      • Unstable angina pectoris
      • Clinically-significant cardiac arrhythmias (patients with atrial fibrillation are eligible)
      • Stroke (including transient ischemic attack [TIA], or other ischemic event)
      • Myocardial infarction
      • Cardiomyopathy

  • No significant 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, or malabsorption syndrome

    • None of the following within 1 year before the first dose of study treatment:

      • Abdominal fistula or genitourinary 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 12 months before the first dose of study treatment
  • Disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement are not eligible

  • No other clinically significant disorders such as:

    • Severe active infection requiring IV 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 or allogeneic stem cell 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)

  • No 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
    • Complete wound healing from prior surgery must be confirmed before the first dose of cabozantinib irrespective of the time from surgery
• No history of severe hypersensitivity reaction to any monoclonal antibody
• No evidence of active malignancy, requiring systemic treatment within 2 years of registration
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study
• No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• No patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include, but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease

Contacts and Locations

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Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	Andrea B Apolo	Alliance for Clinical Trials in Oncology

More Information

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT03866382 History of Changes
Other Study ID Numbers:	NCI-2019-01266; NCI-2019-01266 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); A031702 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A031702 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract )
First Posted:	March 7, 2019
Last Update Posted:	May 24, 2019
Last Verified:	May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL:	https://grants.nih.gov/policy/sharing.htm

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

Additional relevant MeSH terms:

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Carcinoma; Neoplasms; Prostatic Neoplasms; Carcinoma, Squamous Cell; Adenocarcinoma; Urinary Bladder Neoplasms; Carcinoma, Renal Cell; Carcinoma, Transitional Cell; Carcinoma, Neuroendocrine; Penile Neoplasms; Carcinoma, Medullary; Thyroid Neoplasms; Carcinoma, Small Cell; Small Cell Lung Carcinoma; Leydig Cell Tumor	Sertoli Cell Tumor; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Genital Diseases, Male; Prostatic Diseases; Neoplasms, Squamous Cell; Urologic Neoplasms; Urinary Bladder Diseases; Urologic Diseases; Kidney Neoplasms; Kidney Diseases; Neuroendocrine Tumors