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

• ClinicalTrials.gov Identifier: NCT03793166
• Recruitment Status: Recruiting
• First Posted: January 4, 2019
• Last Update Posted: October 15, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
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	Drug: Cabozantinib; Biological: Ipilimumab; Biological: Nivolumab; Other: Quality-of-Life Assessment; Other: Questionnaire Administration	Phase 3

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Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1046 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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]
• Actual Study Start Date: May 9, 2019
• Estimated Primary Completion Date: September 15, 2021
• Estimated Study Completion Date: September 15, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Arm A (nivolumab); INDUCTION: 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.	Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies
Experimental: Arm B (nivolumab, cabozantinib); INDUCTION: 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	Drug: Cabozantinib; Given PO; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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 :

1. 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 ]
   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.
2. Complete response (CR) (randomized patients) [ Time Frame: At 12 months from date of randomization ]
   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.
3. Objective response [ Time Frame: Up to 5 years ]
   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).
4. Proportion of patients who discontinue protocol-directed treatment prior to 1 year from date of study registration [ Time Frame: Up to 5 years ]
   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.
5. Incidence of adverse events [ Time Frame: Up to 5 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 in the protocol.
• 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.
• 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.

Exclusion Criteria:

• 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).

Contacts and Locations

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Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tian Zhang; Alliance for Clinical Trials in Oncology

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03793166 History of Changes
• Other Study ID Numbers: NCI-2018-03694; NCI-2018-03694 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); A031704 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A031704 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract )
• First Posted: January 4, 2019
• Last Update Posted: October 15, 2019
• Last Verified: June 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
• URL: https://grants.nih.gov/policy/sharing.htm

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

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Neoplasms, Second Primary; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Nivolumab; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents