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Cabozantinib and Nivolumab in Treating Patients With Advanced, Recurrent or Metastatic Endometrial Cancer

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ClinicalTrials.gov Identifier: NCT03367741
Recruitment Status : Recruiting
First Posted : December 11, 2017
Last Update Posted : July 13, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase II trial studies how well cabozantinib and nivolumab work in treating patients with endometrial that has come back or 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. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and nivolumab may work better in treating endometrial cancer.

Condition or disease Intervention/treatment Phase
Recurrent Uterine Corpus Carcinoma Stage III Uterine Corpus Cancer AJCC v7 Stage IIIA Uterine Corpus Cancer AJCC v7 Stage IIIB Uterine Corpus Cancer AJCC v7 Stage IIIC Uterine Corpus Cancer AJCC v7 Stage IIIC1 Uterine Corpus Cancer AJCC v7 Stage IIIC2 Uterine Corpus Cancer AJCC v7 Stage IV Uterine Corpus Cancer AJCC v7 Stage IVA Uterine Corpus Cancer AJCC v7 Stage IVB Uterine Corpus Cancer AJCC v7 Drug: Cabozantinib Other: Laboratory Biomarker Analysis Biological: Nivolumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the clinical anti-tumor activity of XL184 (cabozantinib) and nivolumab based on progression free survival (PFS) in patients with advanced, recurrent or metastatic endometrial cancer previously treated with at least one line of platinum-based chemotherapy compared to patients receiving nivolumab alone.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of XL184 and nivolumab in terms of overall response rate (ORR) compared to nivolumab alone.

II. To evaluate overall survival (OS) of patients receiving XL184 and nivolumab compared to patients receiving nivolumab alone.

III. To evaluate the safety of combination treatment using XL184 and nivolumab in patients with advanced, recurrent metastatic endometrial cancer.

IV. To evaluate correlation between PD-L1 expression, CD3, CD4 and CD8 infiltrates and outcome (PFS, ORR, OS).

V. To compare PD-L1 expression, CD3, CD4 and CD8 infiltrates in the primary tumor (archival tissue) and in the tissue from baseline biopsy.

VI. To assess activity (PFS, ORR and OS) of nivolumab alone or in combination with XL184 according to microsatellite instability (MSI)/mismatched repair (MMR) status.

TERTIARY OBJECTIVES:

I. To assess activity (PFS, ORR and OS) of XL184 and nivolumab in patients progressed after previous exposure to anti PD-1, PD-L1 or PD-L2 agents or crossed-over from single agent nivolumab, and in patients with diagnosis of carcinosarcoma.

II. To compare microsatellite (MS) and MMR status, in the primary tumor (archival tissue) and in the tissue from baseline biopsy.

III. To assess the genomic and immune-markers landscape at baseline on tumor tissue and changes in immune landscape in peripheral blood during treatment and correlate with outcome.

OUTLINE: Patients are randomized to 1 of 2 arms.

Arm A: Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (IV) over 60 minutes on days 1 and 15, then on day 1 beginning course 5.

Arm B: Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30-37 days, then every 12 weeks.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase 2 Study of Cabozantinib in Combination With Nivolumab in Advanced, Recurrent Metastatic Endometrial Cancer
Actual Study Start Date : January 26, 2018
Estimated Primary Completion Date : January 23, 2021
Estimated Study Completion Date : January 23, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (cabozantinib, nivolumab)
Patients receive cabozantinib PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15, then on day 1 beginning course 5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib
Giving PO

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm B (nivolumab)
Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Up to 1 year ]

Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 1 year ]
    Summary statistics, such as mean, median, counts and proportion, will be used to summarize the patients. Potential association between variables will be measured using Pearson correlation coefficients, chi-square tests, one- or two-sample t-tests or logistic regression analyses as appropriate. Non-parametric tests such as Spearman correlation coefficients, Fisher's exact tests and Wilcoxon rank sum test may be substituted if necessary. 95% percent confidence intervals will be constructed and selected results will be illustrated using figures and plots.

  2. Overall survival (OS) [ Time Frame: Up to 1 year ]
    Survival estimates will be computed using the Kaplan-Meier method.

  3. Incidence of adverse events [ Time Frame: Up to 1 year ]
    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.

  4. PD-L1 expression, CD3, CD4 and CD8 analysis [ Time Frame: Up to 1 year ]
    Correlated with outcomes (PFS, ORR, OS). The log rank test, cox model or Chi-Square test will apply to access the association between PD-L1, CD3, CD4, CD8 expression and outcome (PFS, OS, ORR) where appropriate.



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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:

  • Patients must have histologically or cytologically confirmed epithelial endometrial carcinoma; all histologies are accepted; patients with diagnosis of endometrial carcinosarcoma will be enrolled in the exploratory cohort (arm C) and will receive combination of cabozantinib and nivolumab
  • Patients must have advance, recurrent or metastatic endometrial cancer
  • Patients must have radiological evidence of disease progression following the most recent treatment
  • Patients must have measurable disease according Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria
  • Must have MS/MMR result available at time of registration; MS/MMR status is to be determined per local practice (i.e. immunohistochemistry [IHC], polymerase chain reaction [PCR], or other methods)
  • Prior therapy: eligible subjects must have had at least one line of platinum-based chemotherapy; this may be adjuvant therapy or first line of cytotoxic therapy for metastatic disease; prior hormonal therapy for metastatic/recurrent disease, prior targeted therapy, and prior radiotherapy are allowed; no maximum number of previous lines of chemotherapies; concomitant chemo-radiation is not considered as previous line of systemic chemotherapy
  • Availability of archival tissue for correlative analysis
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100 x 10^9/L
  • Total bilirubin =< 1.5 ULN (upper limit of normal), unless due to Gilbert's syndrome
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 × institutional upper limit of normal
  • Creatinine =< 1.5 ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Serum albumin > 28 g/L
  • Lipase < 2 ULN
  • Urine protein/ creatinine ratio (UPCR) =< 1
  • Prothrombin time (PT)/ international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 ULN
  • Patient must have disease amenable to biopsy and must agree to have one baseline biopsy
  • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test at screening; WOCBP must agree to use adequate contraception (barrier method of birth control or abstinence) prior to study entry and for the duration of study participation; WOCBP should use an adequate method to avoid pregnancy for 7 months after the last dose of investigational drug; women must not be breastfeeding; women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • CROSS-OVER ELIGIBILITY CRITERIA
  • Patient must provide a tumor biopsy as the time of progression on Arm B; if a patient does not have a tumor lesion amenable of biopsy or it has been unsafe for a biopsy to be performed, cross-over will be allowed

Exclusion Criteria:

  • Patients who have had chemotherapy (including investigational cytotoxic chemotherapy), biologic agents (e.g. targeted therapy or antibodies) or radiotherapy within 4 weeks prior to the first dose of study treatment
  • Patients who have not recovered from adverse events attributed to prior anti-cancer therapy (i.e. have residual toxicities > grade 1, except for alopecia, neuropathy, lymphocytopenia and other non-clinically significant adverse events)
  • Patients who are receiving any other investigational agents
  • Patients should be excluded if they have had prior treatment with anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation; previous treatment with anti-PD-1, anti-PD-L1 or anti-PD-L2 is allowed and patients will be enrolled in the exploratory cohort (arm C) at the time of progression from last line of treatment (treatment with immune check point inhibitor does not have to necessary be the last line of treatment)
  • Patients should be excluded if they have had prior treatment with cabozantinib; previous use of other antiangiogenic agents other than cabozantinib is allowed
  • Any other active malignancy other than the endometrial cancer, that is progressing or requiring active treatment with the exception of basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site
  • Patients with known brain metastases should be excluded from this clinical trial
  • Patients requiring concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, antiplatelet agents (e.g. clopidogrel) or new oral anticoagulants; low-dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib or nivolumab
  • Patients require chronic concomitant treatment of strong CYP450 3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's wort) or inhibitors (eg. ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil and conivaptan)
  • 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 hemorrhage within 3 months before the first dose of study treatment
  • The subject has radiographic evidence of cavitating pulmonary lesion(s)
  • The subject has tumor invading or encasing 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 XL184 (cabozantinib)
  • Subject with extensive pelvic mass at risk of fistulization, or history of bowel obstruction within 3 months prior to the proposed first dose of study treatment
  • 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
      • 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
        • Thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)
    • Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

      • Any of the following within 28 days before the first dose of study treatment

        • Intra-abdominal tumor/metastases invading GI mucosa
        • Active peptic ulcer disease,
        • Inflammatory bowel disease (including ulcerative colitis and Crohn's 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
        • 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
  • Other clinically significant disorders such as:

    • 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
    • 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
    • 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
  • Known active human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS) related illness, or hepatitis B or C infection
  • Administration of a live vaccine within 4 weeks prior to start of protocol therapy
  • Subjects with diagnosis of immunodeficiency or who are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; the following are exceptions to this exclusion criteria: intranasal, inhaled, topical steroids, or local steroids injections (e.g. intra-articular injection); systemic corticosteroids at physiologic dose not to exceed 10 mg/day of prednisone or equivalent; steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
  • History of autoimmune disease, such as, but not restricted to: rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematous, ankylosing spondylitis, scleroderma, or multiple sclerosis requiring treatment within the last two years; patients with vitiligo or diabetes are not excluded; replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; patients with recent history of thyroiditis; subjects with remote history (greater than 5 years) of thyroiditis are not excluded
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • 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 electrocardiogram (EKG)s 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
  • Patient is not able to swallow pills
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with XL184 and nivolumab

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03367741


Locations
United States, California
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Site Public Contact    916-734-3089      
Principal Investigator: Vanessa A. Kennedy         
United States, Illinois
University of Chicago Comprehensive Cancer Center Suspended
Chicago, Illinois, United States, 60637
UC Comprehensive Cancer Center at Silver Cross Suspended
New Lenox, Illinois, United States, 60451
University of Chicago Medicine-Orland Park Suspended
Orland Park, Illinois, United States, 60462
United States, Kansas
University of Kansas Clinical Research Center Recruiting
Fairway, Kansas, United States, 66205
Contact: Site Public Contact    913-945-7552    ctnursenav@kumc.edu   
Principal Investigator: Andrea D. Jewell         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Suspended
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Panagiotis A. Konstantinopoulos         
United States, Missouri
Siteman Cancer Center at West County Hospital Recruiting
Creve Coeur, Missouri, United States, 63141
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Premal H. Thaker         
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Premal H. Thaker         
Siteman Cancer Center-South County Recruiting
Saint Louis, Missouri, United States, 63129
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Premal H. Thaker         
Siteman Cancer Center at Christian Hospital Recruiting
Saint Louis, Missouri, United States, 63136
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Premal H. Thaker         
Siteman Cancer Center at Saint Peters Hospital Recruiting
Saint Peters, Missouri, United States, 63376
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Premal H. Thaker         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: David M. O'Malley         
United States, Pennsylvania
Thomas Jefferson University Hospital Suspended
Philadelphia, Pennsylvania, United States, 19107
United States, Virginia
University of Virginia Cancer Center Suspended
Charlottesville, Virginia, United States, 22908
Virginia Commonwealth University/Massey Cancer Center Suspended
Richmond, Virginia, United States, 23298
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Stephanie Lheureux    416-946-4501 ext 2415    stephanie.lheureux@uhn.ca   
Principal Investigator: Stephanie Lheureux         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Stephanie Lheureux University Health Network Princess Margaret Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03367741     History of Changes
Other Study ID Numbers: NCI-2017-02211
NCI-2017-02211 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PHL-099
10104 ( Other Identifier: University Health Network Princess Margaret Cancer Center LAO )
10104 ( Other Identifier: CTEP )
UM1CA186644 ( U.S. NIH Grant/Contract )
First Posted: December 11, 2017    Key Record Dates
Last Update Posted: July 13, 2018
Last Verified: July 2018

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

Additional relevant MeSH terms:
Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Diseases
Genital Diseases, Female
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs