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

  • STATUS
    Recruiting
  • End date
    Apr 9, 2022
  • participants needed
    1046
  • sponsor
    National Cancer Institute (NCI)
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Updated on 21 April 2021
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platelet count
cancer
calcium
monoclonal antibodies
sunitinib
systemic therapy
measurable disease
carcinoma
interleukin-2
karnofsky performance status
metastasis
neutrophil count
cabozantinib
liver metastasis
tumor cells
pembrolizumab
pd-l1
tremelimumab
programmed cell death 1 ligand 1
nivolumab
ipilimumab
step 2
interleukin 2
atezolizumab
kidney cancer
nephrectomy
metastatic renal cell carcinoma
il-2

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. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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.

Description

PRIMARY OBJECTIVE:

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 progression free survival (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 Response Evaluation Criteria in Solid Tumors [iRECIST] 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 minutes and ipilimumab IV over 30 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 unconfirmed but clinical progression of disease (iuPD) receive cabozantinib orally (PO) daily on days 1-28. Treatment repeats every 28 days until further disease progression or unacceptable toxicity.

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

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

ARM A: Patients receive nivolumab IV over 30 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 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.

Details
Condition Adenocarcinoma, Malignant neoplasm of kidney, Renal Cell Carcinoma, Bone Metastases, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Soft Tissues, Bone Metastasis, Lymph Node Metastasis, Lymph Node Metastases, Metastatic Malignant Neoplasm in the Lymph Nodes, Stage IV Renal Cell Cancer AJCC v8, Kidney Cancer, Metastatic Malignant Neoplasm in Lymph Node, Malignant Adenoma, Renal Cell Cancer, Renal Cancer, Metastatic Malignant Neoplasm in the Viscera, clear cell renal cell carcinoma, visceral metastases
Treatment questionnaire administration, quality-of-life assessment, Ipilimumab, Nivolumab, Cabozantinib
Clinical Study IdentifierNCT03793166
SponsorNational Cancer Institute (NCI)
Last Modified on21 April 2021

Eligibility

 Yes No Not Sure

Inclusion Criteria

Do you have any of these conditions: Metastatic Malignant Neoplasm in the Lymph Nodes or Renal Cell Carcinoma or Lymph Node Metastases or Renal Cell Cancer or visceral metastases or Renal...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Viscera or Bone Metastasis or Stage IV Renal Cell Cancer AJCC v8 or Adenocarcinoma or Kidney Cancer or Renal Cell...?
Do you have any of these conditions: Lymph Node Metastases or Metastatic Malignant Neoplasm in the Lymph Nodes or visceral metastases or Stage IV Renal Cell Cancer AJCC v8 or Renal Cancer...?
Do you have any of these conditions: Renal Cell Cancer or Lymph Node Metastasis or Metastatic Malignant Neoplasm in the Soft Tissues or Metastatic Malignant Neoplasm in Lymph Node or Meta...?
Do you have any of these conditions: Malignant Adenoma or clear cell renal cell carcinoma or Malignant neoplasm of kidney or Metastatic Malignant Neoplasm in the Soft Tissues or Bone Meta...?
Do you have any of these conditions: Renal Cell Cancer or Bone Metastasis or Metastatic Malignant Neoplasm in the Viscera or Malignant Adenoma or Metastatic Malignant Neoplasm in the Soft...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in Lymph Node or Kidney Cancer or Malignant neoplasm of kidney or Malignant Adenoma or Bone Metastases or Adenocarcinoma...?
Do you have any of these conditions: Malignant neoplasm of kidney or Lymph Node Metastasis or Stage IV Renal Cell Cancer AJCC v8 or Renal Cancer or Lymph Node Metastases or Renal Cell Car...?
Do you have any of these conditions: Renal Cell Cancer or Bone Metastases or clear cell renal cell carcinoma or Renal Cell Carcinoma or Metastatic Malignant Neoplasm in the Soft Tissues o...?
Do you have any of these conditions: Kidney Cancer or Stage IV Renal Cell Cancer AJCC v8 or Malignant neoplasm of kidney or Metastatic Malignant Neoplasm in the Viscera or Bone Metastases...?
Do you have any of these conditions: Lymph Node Metastasis or Renal Cell Carcinoma or Bone Metastasis or Metastatic Malignant Neoplasm in the Lymph Nodes or Kidney Cancer or Malignant Ade...?
Do you have any of these conditions: Lymph Node Metastases or Metastatic Malignant Neoplasm in Lymph Node or Adenocarcinoma or Renal Cell Carcinoma or Bone Metastasis or Renal Cell Cancer...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Soft Tissues or Lymph Node Metastases or Adenocarcinoma or Bone Metastasis or Metastatic Malignant Neoplasm in th...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Lymph Nodes or Metastatic Malignant Neoplasm in Lymph Node or Lymph Node Metastases or Stage IV Renal Cell Cancer...?
Do you have any of these conditions: clear cell renal cell carcinoma or Kidney Cancer or Lymph Node Metastases or Renal Cell Cancer or Metastatic Malignant Neoplasm in Lymph Node or Renal...?
Do you have any of these conditions: Bone Metastases or Malignant neoplasm of kidney or Bone Metastasis or Lymph Node Metastasis or Metastatic Malignant Neoplasm in the Lymph Nodes or Ren...?
Do you have any of these conditions: Malignant Adenoma or Metastatic Malignant Neoplasm in the Bone or Metastatic Malignant Neoplasm in the Soft Tissues or Renal Cell Cancer or Bone Metas...?
Is your age greater than or equal to 18 yrs?
Do you have any of these conditions: Malignant Adenoma or Metastatic Malignant Neoplasm in the Bone or Metastatic Malignant Neoplasm in the Lymph Nodes or Renal Cancer or Kidney Cancer or...?
Do you have any of these conditions: Lymph Node Metastasis or Lymph Node Metastases or Metastatic Malignant Neoplasm in the Soft Tissues or Metastatic Malignant Neoplasm in the Lymph Node...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Viscera or Metastatic Malignant Neoplasm in the Bone or Stage IV Renal Cell Cancer AJCC v8 or Adenocarcinoma or v...?
Do you have any of these conditions: Malignant neoplasm of kidney or Lymph Node Metastases or Metastatic Malignant Neoplasm in the Soft Tissues or Malignant Adenoma or Renal Cell Cancer o...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Soft Tissues or Stage IV Renal Cell Cancer AJCC v8 or visceral metastases or Malignant Adenoma or Metastatic Mali...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Lymph Nodes or clear cell renal cell carcinoma or Metastatic Malignant Neoplasm in the Bone or Bone Metastases or...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Soft Tissues or Metastatic Malignant Neoplasm in the Bone or clear cell renal cell carcinoma or Kidney Cancer or ...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Viscera or Malignant neoplasm of kidney or Renal Cell Carcinoma or Metastatic Malignant Neoplasm in the Soft Tiss...?
Do you have any of these conditions: Kidney Cancer or Metastatic Malignant Neoplasm in the Viscera or Malignant Adenoma or Lymph Node Metastasis or Renal Cell Carcinoma or Malignant neopl...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Bone or Renal Cell Carcinoma or clear cell renal cell carcinoma or Malignant neoplasm of kidney or Metastatic Mal...?
Do you have any of these conditions: Adenocarcinoma or Stage IV Renal Cell Cancer AJCC v8 or Malignant Adenoma or Lymph Node Metastasis or Lymph Node Metastases or Metastatic Malignant Ne...?
Do you have any of these conditions: Bone Metastases or clear cell renal cell carcinoma or Metastatic Malignant Neoplasm in the Soft Tissues or Bone Metastasis or Metastatic Malignant Neo...?
Do you have any of these conditions: Metastatic Malignant Neoplasm in the Bone or Metastatic Malignant Neoplasm in Lymph Node or Kidney Cancer or visceral metastases or clear cell renal c...?
Do you have any of these conditions: Renal Cell Cancer or Kidney Cancer or Stage IV Renal Cell Cancer AJCC v8 or Malignant neoplasm of kidney or Metastatic Malignant Neoplasm in Lymph Nod...?
Gender: Male or Female
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
Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria (1 or more of the following: Karnofsky performance status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic treatment for metastatic disease, 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. The only exception is for prior treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or post-operative trials, as long as > 1 year since completion of systemic therapy
No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above 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
Age >= 18 years
Absolute neutrophil count (ANC) >= 1,500/mm^3
Hemoglobin >= 8 g/dL
Platelet count >= 100,000/mm^3
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
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 (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment-related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed
No more than 70 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
Concurrent use of immunosuppressive medication including prednisone above 10 mg daily
History of human immunodeficiency virus (HIV) or active hepatitis B/C, or active tuberculosis (purified protein derivative [PPD] response without active TB is allowed)
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
Moderate of severe hepatic impairment (Child-Pugh B or C)
Lesions encasing or invading any major blood vessels (this does not include tumor thrombus extending into/through renal vein/inferior vena cava [IVC]). Patients with tumor thrombus extending into/through renal vein are considered eligible
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
Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] or non-ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart Association class 3-4 heart failure symptoms
Active treatment with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g., clopidogrel) within 5 days of registration. Allowed anticoagulants include: prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, apixaban. Allowed also in patients with known brain metastases who are on a stable dose of the anticoagulant for at least 1 week prior to registration without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
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systemic therapy
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interleukin-2
karnofsky performance status
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cabozantinib
liver metastasis
tumor cells
pembrolizumab
pd-l1
tremelimumab
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interleukin 2
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