Clinical Trials /

Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors

NCT03866382

Description:

This phase II trial studies how well cabozantinib works in combination with nivolumab and ipilimumab 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 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.

Related Conditions:
  • Bladder Adenocarcinoma
  • Bladder Small Cell Neuroendocrine Carcinoma
  • Bladder Squamous Cell Carcinoma
  • Chromophobe Renal Cell Carcinoma
  • Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
  • Malignant Sertoli Cell Tumor
  • Malignant Testicular Leydig Cell Tumor
  • Papillary Renal Cell Carcinoma
  • Penile Carcinoma
  • Prostate Neuroendocrine Carcinoma
  • Prostate Small Cell Carcinoma
  • Sarcomatoid Renal Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors
  • Official Title: A Phase II Study of Ipilimumab, Cabozantinib, and Nivolumab in Rare Genitourinary Cancers (ICONIC)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01266
  • SECONDARY ID: NCI-2019-01266
  • SECONDARY ID: A031702
  • SECONDARY ID: A031702
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03866382

Conditions

  • Bladder Adenocarcinoma
  • Bladder Mixed Adenocarcinoma
  • Bladder Small Cell Carcinoma
  • Bladder Squamous Cell Carcinoma
  • Bone Lesion
  • 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 Carcinoma
  • Metastatic Bladder Squamous Cell Carcinoma
  • Metastatic Infiltrating Bladder Urothelial Carcinoma, Clear Cell Variant
  • Metastatic Infiltrating Bladder Urothelial Carcinoma, Lipid-Rich Variant
  • Metastatic Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant
  • Metastatic Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant
  • Metastatic Infiltrating Bladder Urothelial Carcinoma, Sarcomatoid Variant
  • Metastatic Kidney Medullary Carcinoma
  • Metastatic Malignant Genitourinary System Neoplasm
  • Metastatic Penile Carcinoma
  • Metastatic Prostate Small Cell Carcinoma
  • Metastatic Sarcomatoid Renal Cell 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

Interventions

DrugSynonymsArms
CabozantinibTreatment (cabozantinib, nivolumab, ipilimumab)
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Treatment (cabozantinib, nivolumab, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (cabozantinib, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (cabozantinib, nivolumab, ipilimumab)

Purpose

This phase II trial studies how well cabozantinib works in combination with nivolumab and ipilimumab 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 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.

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 objective
      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 and on
      days 1-28 of subsequent cycles. Patients also receive nivolumab intravenously (IV) over 30
      minutes on day 1 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Patients then
      receive nivolumab IV over 30 minutes on day 1 of subsequent cycles. Treatment repeats 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib, nivolumab, ipilimumab)ExperimentalPatients receive cabozantinib PO QD on days 1-21 of cycles 1-4 and on days 1-28 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Patients then receive nivolumab IV over 30 minutes on day 1 of subsequent cycles. Treatment repeats 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.
  • Cabozantinib
  • Cabozantinib S-malate
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

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

               -  One measurable site of disease as per Response Evaluation Criteria in Solid
                  Tumors (RECIST) version (v) 1.1

               -  One bone lesion on bone scan (tec99 or sodium fluoride [NaF] positron emission
                  tomography [PET]/computed tomography [CT], CT, or magnetic resonance imaging
                  [MRI]) for the bone-only cohort

               -  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)

               -  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 =< 7 days prior to
             registration

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:The median its 95% confidence interval will be determined and will be summarized using the Kaplan-Meier estimator.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:The median its 95% confidence interval will be determined and will be summarized using the Kaplan-Meier estimator.
Measure:Clinical benefit rate (CBR)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Incidence of adverse events (AE)
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated