Clinical Trials /

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

NCT03367741

Description:

This randomized phase II trial studies how well cabozantinib s-malate and nivolumab work in treating patients with endometrial that has come back (recurrent) or spread to other places in the body (advanced or metastatic). 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, 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 and nivolumab may work better in treating endometrial cancer.

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib S-malate and Nivolumab in Treating Patients With Advanced, Recurrent or Metastatic Endometrial Cancer
  • Official Title: A Randomized Phase 2 Study of Cabozantinib in Combination With Nivolumab in Advanced, Recurrent Metastatic Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-02211
  • SECONDARY ID: NCI-2017-02211
  • SECONDARY ID: PHL-099
  • SECONDARY ID: 10104
  • SECONDARY ID: 10104
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT03367741

Conditions

  • 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

Interventions

DrugSynonymsArms
CabozantinibArm A (cabozantinib s-malate, nivolumab)
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Arm A (cabozantinib s-malate, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (cabozantinib s-malate, nivolumab)

Purpose

This randomized phase II trial studies how well cabozantinib s-malate 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. Immunotherapy with monoclonal antibodies, such as nivolumab, 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 and nivolumab may work better in treating endometrial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the clinical anti-tumor activity of cabozantinib s-malate (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.

      EXPLORATORY 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 s-malate 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 cycle
      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, cycles 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 8-12
      weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (cabozantinib s-malate, nivolumab)ExperimentalPatients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate
  • Nivolumab
Arm B (nivolumab)ExperimentalPatients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab

Eligibility 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

          -  The effects of cabozantinib and nivolumab on the developing human fetus are unknown;
             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
             because of their poor prognosis and because of the possible increased risk of bleeding
             if treatment with antiangiogenic agents is provided

          -  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 (e.g. ketoconazole, miconazole,
             itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir,
             saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir,
             troleandomycin, mibefradil and conivaptan); because the lists of these agents are
             constantly changing, it is important to regularly consult a frequently-updated list,
             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 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 mmHg systolic, or > 90 mmHg 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 (e.g., 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 because XL184 and nivolumab are agents
             with the 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 XL184 and nivolumab, breastfeeding should be discontinued
             if the mother is treated with XL184 and nivolumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Up to 1 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to 1 year
Safety Issue:
Description:Survival estimates will be computed using the Kaplan-Meier method.
Measure:Incidence of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.
Measure:PD-L1 expression, CD3, CD4 and CD8 analysis
Time Frame:Up to 1 year
Safety Issue:
Description: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.

Details

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

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