Trial record 16 of 71 for:    cabozantinib

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02496208
First received: July 8, 2015
Last updated: August 24, 2016
Last verified: August 2016
  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. Monoclonal antibodies, such as nivolumab and ipilimumab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether giving cabozantinib-s-malate and nivolumab alone or with ipilimumab works better in treating patients with genitourinary tumors.

Condition Intervention Phase
Malignant Reproductive System Neoplasm
Malignant Urinary System Neoplasm
Metastatic Urethral Neoplasm
Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter
Progressive Neoplastic Disease
Recurrent Bladder Carcinoma
Recurrent Urethra Carcinoma
Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter
Regional Urothelial Carcinoma of the Renal Pelvis and Ureter
Solid Neoplasm
Stage III Bladder Urothelial Carcinoma
Stage III Urethral Cancer
Stage IV Bladder Urothelial Carcinoma
Stage IV Urethral Cancer
Urethral Urothelial Carcinoma
Drug: Cabozantinib S-malate
Biological: Ipilimumab
Other: Laboratory Biomarker Analysis
Biological: Nivolumab
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • RP2D defined as the highest dose for which no more than 1/6 patients experience a DLT assessed using National Cancer Institute CTCAE version 4.0 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Clinical response rate assessed by RECIST 1.1 and irRC [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    The response rate may be used to guide the further development of the combinations.

  • Fraction of patients who have been identified as being alive and progression free at two months [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    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 PFS will also be presented as a secondary endpoint, in addition to reporting the fraction without progression at two months.


Estimated Enrollment: 66
Study Start Date: July 2015
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part I (cabozantinib-s-malate, nivolumab)
Patients receive cabozantinib-s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL184
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
Experimental: Part II (cabozantinib-s-malate, nivolumab, ipilimumab)
Patients receive cabozantinib-s-malate PO QD on days 1-21, nivolumab IV over 60 minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of 4 courses with ipilimumab, patients continue receiving cabozantinib-s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 42 courses in the absence of disease progression or unacceptable toxicity.
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
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

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 and separately the combination of cabozantinib, nivolumab and ipilimumab in patients with genitourinary tumors.

SECONDARY OBJECTIVES:

I. Preliminarily evaluate the activity of these two combinations as determined by the objective response rate in patients with advanced/refractory metastatic urothelial carcinoma in the second-line and beyond setting using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the modified Immune-Related Response Criteria (irRC), derived from RECIST 1.1.

II. To evaluate the activity of these combinations as determined by progression free survival (PFS) and overall survival (OS) in patients with advanced/refractory metastatic urothelial carcinoma in the second-line and beyond setting.

III. 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).

IV. 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.

V. To test the feasibility of automated density and volume application (ADaVA) as a means of assessing tumor response.

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 60 minutes on days 1 and 15. Courses repeat every 28 days 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 60 minutes on day 1, and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of 4 courses with ipilimumab, patients continue receiving cabozantinib-s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 42 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 16 weeks or 100 days and then every 2 months thereafter.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis
    • 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)
  • Patients must have failed at least one standard therapy or no standard treatment exists that has been shown to prolong survival; 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)
  • 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) or < 5.0 x ULN in patients with Gilbert's syndrome
  • Creatinine =< 1.5 x ULN OR creatinine clearance >= 40 mL/min/1.73 m^2 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)
  • Serum calcium >= LLN
  • Serum magnesium >= LLN
  • Serum potassium >= LLN
  • 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
  • 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 31 weeks 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 23 weeks 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 23 or 31 weeks 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 23 or 31 weeks 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 proto-oncogene (MET) or vascular endothelial growth factor receptor (VEGFR) inhibitors are not eligible for phase II 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
  • 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 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 >= 1.3 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 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 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
  • 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 28 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 if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications
      • 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; breastfeeding should be discontinued if the mother is treated with cabozantinib
  • Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART), cluster of differentiation (CD)4 counts are greater than 350 and viral load is undetectable
  • Patients are excluded if they have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • 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, should be excluded; 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

    • Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible
    • Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
  • Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
  • Patients are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with mi
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02496208

Locations
United States, California
City of Hope Comprehensive Cancer Center Suspended
Duarte, California, United States, 91010
University of California Davis Comprehensive Cancer Center Suspended
Sacramento, California, United States, 95817
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: Andrea B. Apolo    800-411-1222      
Principal Investigator: Andrea B. Apolo         
NCI - Center for Cancer Research Recruiting
Bethesda, Maryland, United States, 20892
Contact: Andrea B. Apolo    800-411-1222      
Principal Investigator: Andrea B. Apolo         
United States, New Jersey
Rutgers Cancer Institute of New Jersey Suspended
New Brunswick, New Jersey, United States, 08903
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Amir Mortazavi    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Amir Mortazavi         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Andrea Apolo National Cancer Institute LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02496208     History of Changes
Other Study ID Numbers: NCI-2014-02379  NCI-2014-02379  P141706  150160  9681  9681  UM1CA186712  UM1CA186716  UM1CA186717  ZIABC011078 
Study First Received: July 8, 2015
Last Updated: August 24, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Carcinoma, Transitional Cell
Urethral Neoplasms
Urinary Bladder Neoplasms
Kidney Neoplasms
Ureteral Neoplasms
Urologic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urogenital Neoplasms
Neoplasms by Site
Urethral Diseases
Urologic Diseases
Urinary Bladder Diseases
Kidney Diseases
Ureteral Diseases
Antibodies, Monoclonal
Nivolumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 25, 2016