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Official Title

A Phase II Study of Ipilimumab, Cabozantinib, and Nivolumab in Rare Genitourinary Cancers (ICONIC)

Phase
Phase 2
Sponsor
National Cancer Institute (NCI)
Enrollment
314
Timeline
May 2019 → Feb 2026
About This Study

This phase II trial studies how well cabozantinib works in combination with nivolumab and ipilimumab in treating patients with rare genitourinary (GU) tumors that has spread from where it first started (primary site) 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.

Eligibility Criteria

Inclusion Criteria

  • 1Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:
  • 2One measurable site of disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
  • 3One bone lesion on bone scan (tec99 or sodium fluoride \[NaF\] PET/CT, CT or MRI) for the bone-only cohort.
  • 4Histologically confirmed diagnosis of one of the following metastatic cohorts:
  • 5Small cell/ neuroendocrine carcinoma of the bladder (Cohort A)- All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded
  • 6Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra clear cell adenocarcinoma (Cohort B) - must be pure (per World Health Organization \[WHO\] definition), (i.e. urothelial carcinoma with glandular differentiation is not considered a pure adenocarcinoma
  • 7Squamous cell carcinoma of the bladder (Cohort C) - must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma)
  • 8Plasmacytoid urothelial carcinoma (Cohort D) - Tumor should show predominantly \> or equal \~ 50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well)
  • 9Any penile cancer (Cohort E)
  • 10Sarcomatoid renal cell carcinoma (Cohort F) - Tumor should be predominantly sarcomatoid \~ 50% (including rhabdoid differentiation) is also unclassified renal cell carcinomas (RCCs): all (assuming they are high grade with metastasis) malignant angiomyolipomas are allowed
  • 11Other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to (Cohort G) : Micropapillary (Tumor should show predominantly \> or equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell and nested variants (Tumor should predominantly \> or equal 50% show these features), large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer (Only treatment-naïve primary small cell of prostate with any amount of small cell component allowed. Post-treatment small cell prostatic carcinomas are not allowed), Malignant testicular Sertoli or Leydig cell tumors, and papillary and chromophobe RCC
  • 12Note: Translocation positive renal cell carcinoma patients are eligible. However, AREN1721 should be considered before this trial
  • 13Sarcomatoid urothelial carcinoma (Cohort H) - Tumor should show predominantly \~ 50% sarcomatoid differentiation
  • 14Renal medullary carcinoma (Cohort I) - Per World Health Organization (WHO) definition, ideally confirmed with immunostains
  • 15Bone-only metastatic GU tumors (non-prostate) (Cohort J) - All genitourinary histologies, except prostate are eligible
  • 16Renal Collecting Duct Carcinoma (Cohort K) - Per WHO definition (medullary involvement, predominant tubular morphology, desmoplastic stromal reaction, high grade cytology, infiltrative growth pattern, and absence of other renal cell carcinoma subtype or urothelial carcinoma)
  • 17Urethra carcinoma (Cohort L) - May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder
  • 18H\&E slides from diagnostic tumor tissue for retrospective central pathology review
  • 19Patients may have received up to 2 systemic anti-cancer treatments or be treatment naive. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin-eligible)
  • 20Age \>= 18 years
  • 21Patients must be able to swallow oral formulation of the tablets
  • 22Karnofsky performance status \>= 80%
  • 23Absolute neutrophil count (ANC) \>= 1,000/mcL
  • 24Platelet count \>= 75,000/mcL
  • 25Total 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
  • 26Aspartate 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)
  • 27Creatinine =\< 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
  • 28Hemoglobin \>= 9 g/dL (transfusion of packed red blood cells \[PRBCs\] allowed)
  • 29Serum albumin \>= 3.2 g/dL
  • 30Lipase and amylase =\< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or clinical evidence of pancreatitis
  • 31Prior 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
  • 32No prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4 inhibitors with the exception of patients with "urothelial carcinoma" histology (cohorts D, H, J, L)
  • 33Human 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
  • 34Patients 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
  • 35Patients 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
  • 36Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, and gastrointestinal (GI) obstruction, within 12 months are not eligible
  • 37Women of childbearing potential must have a negative pregnancy test =\< 7 days prior to registration
  • 38Women 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
  • 39Pregnant 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
  • 40The 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
  • 41The patient has received no radiation therapy:
  • 42To 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
  • 43To 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
  • 44To the abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy
  • 45To any other site(s) within 2 weeks before the first dose of study treatment
  • 46The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment
  • 47The 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
  • 48The 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
  • 49The patient has not received any other type of investigational agent within 14 days before the first dose of study treatment
  • 50The 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
  • 51The patient may not have active brain metastases or epidural disease. Patients with brain metastases previously treated with whole brain radiation or radiosurgery 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 MRI scans for subjects with known brain metastases is required to confirm eligibility
  • 52No 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
  • 53No 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
  • 54Because 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
  • 55The patient has not experienced any of the following:
  • 56Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  • 57Hemoptysis of \>= 0.5 teaspoon (2.5 mL) of red blood per day within 1 months before the first dose of study treatment
  • 58Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  • 59The patient has no tumor invading any major blood vessels
  • 60The 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. Patients with rectal tumor masses are not eligible
  • 61The patient has no uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
  • 62Cardiovascular disorders including:
  • 63Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening.
  • 64Concurrent 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
  • 65The 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
  • 66Any history of congenital long QT syndrome
  • 67Any of the following within 6 months before registration of study treatment:
  • 68Unstable angina pectoris
  • 69Clinically-significant cardiac arrhythmias (patients with atrial fibrillation are eligible)
  • 70Stroke (including transient ischemic attack \[TIA\], or other ischemic event)
  • 71Myocardial infarction
  • 72Cardiomyopathy
  • 73No significant gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
  • 74Any of the following that have not resolved within 28 days before the first dose of study treatment:
  • 75Active peptic ulcer disease
  • 76Acute diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or malabsorption syndrome
  • 77None of the following within 2 years before the first dose of study treatment:
  • 78Abdominal fistula or genitourinary fistula
  • 79Gastrointestinal perforation
  • 80Bowel obstruction or gastric outlet obstruction
  • 81Intra-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 2 years before the first dose of study treatment
  • 82Disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement are not eligible
  • 83No other clinically significant disorders such as:
  • 84Severe active infection requiring IV systemic treatment within 14 days before the first dose of study treatment
  • 85Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
  • 86History of organ or allogeneic stem cell transplant
  • 87Concurrent 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)
  • 88No history of major surgery as follows:
  • 89Major 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
  • 90Minor 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
  • 91Complete wound healing from prior surgery must be confirmed before the first dose of cabozantinib irrespective of the time from surgery
  • 92No history of severe hypersensitivity reaction to any monoclonal antibody
  • 93No evidence of active malignancy, requiring systemic treatment within 2 years of registration
  • 94No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study
  • 95No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. If HBV sAG is positive, subsequent ribonucleic acid (RNA) polymerase chain reaction (PCR) must be negative
  • 96No 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

Locations

576 sites participating in this study

Emory University Hospital Midtown

Atlanta, Georgia 30308

Recruiting

Mehmet A. Bilen

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia 30322

Recruiting

Mehmet A. Bilen

Emory Saint Joseph's Hospital

Atlanta, Georgia 30342

Suspended
Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →