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Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study

NCT03793166

Description:

This phase III trial compares the usual treatment (treatment with ipilimumab and nivolumab followed by nivolumab alone) to treatment with ipilimumab and nivolumab, followed by nivolumab with cabozantinib in patients with untreated renal cell carcinoma that has spread to other parts of the body. The addition of cabozantinib to the usual treatment may make it work better. 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. Drugs used in chemotherapy, such as cabozantinib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known how well the combination of cabozantinib and nivolumab after initial treatment with ipilimumab and nivolumab works in treating patients with renal cell cancer that has spread to other parts of the body.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Ipilimumab Followed by Nivolumab Versus Cabozantinib and Nivolumab in Treating Patients With Metastatic Untreated Renal Cell Cancer
  • Official Title: PD-Inhibitor (Nivolumab) and Ipilimumab Followed by Nivolumab vs. VEGF TKI Cabozantinib With Nivolumab: A Phase III Trial in Metastatic Untreated Renal Cell Cancer [PDIGREE]

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-03694
  • SECONDARY ID: NCI-2018-03694
  • SECONDARY ID: A031704
  • SECONDARY ID: A031704
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03793166

Conditions

  • Clear Cell Renal Cell Carcinoma
  • Metastatic Malignant Neoplasm in Lymph Node
  • Metastatic Malignant Neoplasm in the Bone
  • Metastatic Malignant Neoplasm in the Soft Tissues
  • Metastatic Malignant Neoplasm in the Viscera
  • Sarcomatoid Renal Cell Carcinoma
  • Stage IV Renal Cell Cancer AJCC v8

Interventions

DrugSynonymsArms
CabozantinibArm B (nivolumab, cabozantinib)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm A (nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab)

Purpose

This phase III trial studies how well nivolumab and ipilimumab, followed by nivolumab versus cabozantinib and nivolumab, work in treating patients with renal cell cancer that is untreated and has spread to other parts of the body. 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. Drugs used in chemotherapy, such as cabozantinib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known how well cabozantinib and nivolumab work in treating patients with untreated renal cell cancer that has spread to other parts of the body.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the overall survival (OS) in patients with metastatic renal cell cancer (RCC)
      treated with ipilimumab-nivolumab followed by either nivolumab versus cabozantinib-nivolumab.

      SECONDARY OBJECTIVES:

      I. To determine PFS of patients treated with nivolumab versus nivolumab-cabozantinib.

      II. To evaluate the 12-month complete response rate in patients treated with
      ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed
      by nivolumab (patients who have complete response [CR] and relapse before 12 months will not
      be counted as a CR at 12-months).

      III. To evaluate the rates of discontinuing therapy at 1 year. IV. To compare objective
      response rates (ORR, assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1
      and Immune-Related Response Evaluation Criteria in Solid Tumors [irRECIST] criteria) for
      patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus
      ipilimumab-nivolumab followed by nivolumab.

      V. To document the adverse event profile of ipilimumab-nivolumab followed by
      cabozantinib-nivolumab.

      BIOMARKER OBJECTIVES:

      I. To evaluate biomarkers associated with exceptional responses in both arms (exceptional
      responses defined as CRs with treatment discontinuation at 12 months or 24 months).

      II. To evaluate whether baseline IL-6 is predictive of outcome in patients treated with
      cabozantinib-containing regimen.

      QUALITY OF LIFE (QOL) OBJECTIVES:

      I. To compare health-related quality of life at 18 months post-registration as assessed by
      the Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (FKSI-19) between
      patients randomized to nivolumab (nivo) versus (vs) cabozantinib (cabo)/nivo.

      II. To compare health-related quality of life as assessed by the FKSI-19 between patients
      randomized to nivo vs cabo/nivo at other time points.

      III. To compare patient-reported fatigue using Patient-Reported Outcomes Measurement
      Information System (PROMIS)-Fatigue between patients randomized to nivo vs cabo/nivo.

      IV. To compare quality-adjusted survival (overall survival x utility score assessed by
      EuroQol five-dimensional questionnaire [EQ5D-5L]) between patients randomized to nivo vs
      cabo/nivo.

      OUTLINE:

      INDUCTION: Patients receive nivolumab intravenously (IV) over 30 or 60 minutes and ipilimumab
      IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the
      absence of disease progression or unacceptable toxicity.

      TREATMENT:

      Patients with progression of disease (PD) receive cabozantinib orally (PO) daily on days
      1-28. Treatment repeats every 28 days until further disease progression or unacceptable
      toxicity.

      Patients with CR receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every
      28 days in the absence of disease progression or unacceptable toxicity.

      Patients with non-CR/non-PD are randomized to 1 of 2 arms.

      ARM A: Patients receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every
      28 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive nivolumab IV over 30 or 60 minutes on day 1 and cabozantinib PO daily
      on days 1-28. Treatment repeats every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab)Active ComparatorINDUCTION: Patients receive nivolumab IV over 30 or 60 minutes and ipilimumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. TREATMENT: Patients with PD receive cabozantinib PO daily on days 1-28. Treatment repeats every 28 days until further disease progression or unacceptable toxicity. Patients with CR receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients with non-CR/non-PD receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
Arm B (nivolumab, cabozantinib)ExperimentalINDUCTION: Patients receive nivolumab IV over 30 or 60 minutes and ipilimumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. TREATMENT: Patients with PD receive cabozantinib PO daily on days 1-28. Treatment repeats every 28 days until further disease progression or unacceptable toxicity. Patients with CR receive nivolumab IV over 30 or 60 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients with non-CR/non-PD receive nivolumab IV over 30 or 60 minutes on day 1 and cabozantinib PO daily on days 1-28. Treatment repeats every 28 days in the absence of
  • Cabozantinib
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  STEP I REGISTRATION CRITERIA

          -  Histologically documented renal cell carcinoma with clear cell component, including
             patients who have sarcomatoid features.

          -  Any metastatic disease, including visceral, lymph node, other soft tissue and bone,
             measurable per RECIST 1.1.

          -  Measurable disease as defined.

          -  Intermediate or poor risk patients per International Metastatic Renal Cell Carcinoma
             Database (IMDC) criteria will be eligible (1 or more of the following: Karnofsky
             performance status (KPS) < 80, < 1 year from diagnosis to systemic treatment,
             hemoglobin less than lower limit of normal (LLN), corrected calcium concentration
             greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN,
             platelet count > ULN).

          -  Central nervous system (CNS) disease permitted, if stable and not otherwise causing
             symptoms or needing active treatment.

          -  Karnofsky performance status >= 70%.

          -  No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not
             limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab,
             tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting
             T-cell co-stimulation or checkpoint pathways.

          -  No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days]
             and prior adjuvant sunitinib > 180 days since completion are allowed).

          -  No cancer therapy less than 28 days prior to registration; this includes radiation
             therapy, except for bone lesions less than 14 days prior to registration. There must
             be a complete recovery and no ongoing complications from radiotherapy.

          -  Not pregnant and not nursing, because this study involves an agent that has known
             genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing
             potential only, a negative serum or urine pregnancy test done =< 14 days prior to
             registration is required.

          -  None of the following:

               -  Active autoimmune disease requiring ongoing therapy.

               -  Ongoing acute toxicity > grade 2 from previous treatment.

               -  History of severe allergic, anaphylactic or other hypersensitivity reactions to
                  chimeric or humanized antibodies.

               -  History of human immunodeficiency virus (HIV) or active hepatitis B/C, or
                  tuberculosis.

               -  Concurrent use of immunosuppressive medication including prednisone above 10 mg
                  daily.

               -  Uncontrolled adrenal insufficiency.

               -  Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP
                  > 90 mmHg).

               -  Major surgery less than 28 days prior to registration.

               -  Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to
                  registration.

               -  Any arterial thrombotic events within 180 days prior to registration.

               -  Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks
                  prior to registration.

               -  Cavitating pulmonary lesions or known endotracheal or endobronchial disease
                  manifestations.

               -  Lesions encasing or invading any major blood vessels.

               -  Moderate of severe hepatic impairment (child-Pugh B or C).

               -  Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in
                  the 180 days prior to registration. (Any asymptomatic, treated pulmonary embolism
                  or asymptomatic, treated deep venous thrombosis > 30 days prior to registration
                  allowed).

               -  Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.

               -  Unstable cardiac arrhythmia within 6 months prior to registration.

               -  Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs of
                  pulmonary hemorrhage =< 90 days prior to registration.

               -  History of abdominal fistula, gastrointestinal perforation, intra-abdominal
                  abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior
                  to registration.

               -  Active peptic ulcer disease, inflammatory bowel disease, or malabsorption
                  syndrome within 28 days prior to registration.

               -  Untreated hypothyroidism, evidence of pancreatitis, history of organ transplant,
                  or history of congenital QT syndrome.

               -  Active treatment with warfarin or any oral factor Xa inhibitors (treatment with
                  low molecular weight heparin [LMWH] is allowed).

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3.

          -  Platelet Count >= 100,000/mm^3.

          -  Hemoglobin >= 8 g/d.

          -  Calculated (Calc.) creatinine clearance >= 30 mL/min.

          -  Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.

          -  Total Bilirubin =< 1.5 x upper limit of normal (ULN).

          -  Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of
             normal (ULN) or < 5 x ULN if hepatic metastases present.

          -  Creatine kinase MB (CK-MB) and troponin =< upper limit of normal (ULN).

          -  STEP 2 REGISTRATION ELIGIBILITY CRITERIA

          -  Successful completion of at least 1 cycle of ipilimumab/nivolumab.

          -  Resolution of any treatment-related adverse events to grade 1 or less per dose
             modification section.

          -  No more than 56 days from last dose of ipilimumab/nivolumab.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From registration to date of death from any cause for non-randomized patients, from time of randomization until death from any cause for randomized patients, assessed up to 5 years
Safety Issue:
Description:OS of patients who achieve complete response (CR) and progressive disease (PD) from ipilimumab-nivolumab induction phase will be summarized. The stratified log-rank statistic will be the primary analysis to compare the hypothesis on OS with the stratification factors (presence of bone metastases and IMDC risk criteria). The Kaplan-Meier product-limit estimator will be used to estimate the OS. A stratified proportional hazards model will be used to generate estimates for the OS hazard ratio. For the randomized patients, OS will be calculated and compared from the time of randomization until the time of an OS event or time of last-follow-up, whatever occurs first. For the patients who were initially CR or PD, OS will be measured from the time of study registration. A comparison of OS will be made across the patient groups (randomized patients, patients initially CR, and patients initially PD).

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From date of registration to date of progression or death from any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Progression will be defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. PFS of patients who achieve CR and PD from ipilimumab-nivolumab induction phase will be summarized (secondary analysis). The Kaplan-Meier product-limit estimator will be used to estimate the PFS distribution. A stratified proportional hazards model will be used to generate estimates for the PFS hazard ratio. For the randomized patients, PFS will be calculated and compared from the time of randomization until the time of a PFS event or time of last-follow-up, whatever occurs first. For the patients who were initially CR or PD, PFS will be measured from the time of study registration. A comparison of PFS will be made across the patient groups (randomized patients, patients initially CR, and patients initially PD). For this comparison, PFS will be measured from time of study registration all the patients, regardless of whether they were randomized or not.
Measure:Complete response (CR) (randomized patients)
Time Frame:At 12 months from date of randomization
Safety Issue:
Description:Patients who had a CR prior to 12 months but have experienced a disease recurrence prior to 12 months, will not be considered to be a CR at 12 months. The Cochran-Mantel-Haenszel test will be used to compare the two arms on the proportion of patients who have a 12-month CR adjusting on the stratification factors.
Measure:Objective response
Time Frame:Up to 5 years
Safety Issue:
Description:Defined as the best response observed that has been confirmed by a scan performed 4 or more weeks after the observation of the initial response. The objective response will be determined using RECIST 1.1. In addition, objective responses will also be determined using Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST).
Measure:Proportion of patients who discontinue protocol-directed treatment prior to 1 year from date of study registration
Time Frame:Up to 5 years
Safety Issue:
Description:Patients who stop their protocol directed treatment for any reason prior to one year from study registration will be considered to have discontinued their treatment. The Cochran-Mantel-Haenszel test will also be used to compare the proportion of patients who discontinue their treatment prior to one-year after study registration.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. A Fisher's exact test will be used to compare the two treatment arms on the proportion of patient with a grade 3 or higher adverse event.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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