A Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination With Anti-PD-1 Antibody (Nivolumab) or in Combination With Nivolumab and Anti-CTLA4 Antibody (Ipilimumab) in Patients With Select Advanced or Metastatic Solid Tumours

Official Title

A Phase 1/2, Open-label, Multicentre Study of the Combination of NKTR-214 and Nivolumab or the Combination of NKTR-214, Nivolumab, and Ipilimumab in Patients With Select Locally Advanced or Metastatic Solid Tumour Malignancies

Summary:

In this four part study, NKTR-214 will be administered in combination with nivolumab in Parts 1 & 2, and with nivolumab and ipilimumab in Parts 3 & 4. In Part 1, the safety, efficacy and recommended Phase 2 dose (RP2D) of NKTR-214 in combination with nivolumab will be determined. In Part 2, the clinical benefit, safety, and tolerability of combining NKTR-214 with nivolumab at the RP2D in select patients with Melanoma, Renal Cell Carcinoma, Non-Small Cell Lung Cancer, Urothelial Carcinoma, or Triple Negative Breast Cancer. In Part 3, the safety, efficacy and RP2D of NKTR-214 in combination with nivolumab and ipilimumab will be determined. In Part 4, the clinical benefit, safety, and tolerability of the triplet combination will be evaluated in select patients with RCC or NSCLC. All three drugs target the immune system and may act synergistically to promote anti-cancer effects.

Trial Description

Primary Outcome:

  • Safety of NKTR-214 in combination with nivolumab as evaluated by incidence of drug-related Adverse Events (AEs), Serious Adverse Events (SAEs), and adverse events leading to discontinuation, deaths, and clinical laboratory test abnormalities
  • Safety of NKTR-214 in combination with nivolumab and ipilmumab as evaluated by incidence of drug-related AEs, SAEs, and adverse events leading to discontinuation, deaths, and clinical laboratory test abnormalities
  • Tolerability of NKTR-214 in combination with nivolumab as evaluated by incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities
  • Tolerability of NKTR-214 in combination with nivolumab and ipilmumab as evaluated by incidence of Dose Limiting Toxicities (DLTs), drug-related AEs, SAEs, adverse events leading to discontinuation, deaths and clinical laboratory test abnormalities
  • Efficacy of NKTR-214 in combination with nivolumab as assessed by the Objective Response Rate (ORR) based on RECIST 1.1
  • Efficacy of NKTR-214 in combination with nivolumab and ipilmumab as assessed by the Objective Response Rate (ORR) based on RECIST 1.1
Secondary Outcome:
  • Overall Survival (OS)
  • Progression-Free Survival (PFS)
NKTR-214 is a cytokine (investigational agent) that is designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumour effects. Nivolumab is a full human monoclonal antibody that binds to a molecule called PD-1 (programmed cell death protein 1) on immune cells and promotes anti-tumour effects. Part 1: Dose escalation of NKTR-214 in combination with nivolumab. A total of 38 eligible patients were enrolled into one of five dose regimens of NKTR-214 in combination with nivolumab (0.006 mg/kg NKTR-214 every 3 weeks (q3w) with 240 mg nivolumab every two weeks (q2w), 0.003 mg/kg NKTR-214 q2w with 240 mg nivolumab q2w, 0.006 mg/kg NKTR-214 q2w with 240 mg nivolumab q2w, 0.006 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w, 0.009 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w). The first part of the study evaluated the safety and efficacy profile of the combination and it was determined that a dose of 0.006 mg/kg NKTR-214 q3w with 360 mg nivolumab q3w, was the Recommended Phase 2 Dose (RP2D), to be studied in Part 2 of the study. Part 2: Dose expansion of NKTR-214 in combination with nivolumab. Patients across a total of five specific tumour types (Melanoma, Renal Cell Carcinoma (RCC), Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma, and Triple Negative Breast Cancer (TNBC)) will be enrolled to receive the RP2D of NKTR-214 in combination with nivolumab. Approximately 350 eligible patients who are either Immuno-oncology (I-O) therapy naïve or anti-PD-1 or anti-PD-L1 relapsed/refractory will be enrolled in the Dose Expansion (Part 2) into one of thirteen cohorts as follows:
  • Melanoma:1st-line
  • Melanoma: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
  • RCC: 1st-line I-O therapy naïve
  • RCC: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
  • NSCLC 1st-line (PD-L1 ≥ 50%)
  • NSCLC 1st-line (PD-L1< 1%)
  • NSCLC 1st-line (PD-L1 ≥ 1%
  • < 50%)
  • NSCLC: 2nd-line I-O therapy naïve
  • NSCLC: 2nd- and 3rd-line anti-PD-1 or anti-PD-L1 relapsed/refractory
  • Urothelial Carcinoma (Bladder): 1st-line I-O therapy naïve
  • Urothelial Carcinoma (Bladder): 1st-line cisplatin-ineligible I-O therapy naïve
  • Urothelial Carcinoma (Bladder): 3rd-Line anti-PD-1 or anti-PD-L1 relapsed/refractory
  • TNBC: 1st- and 2nd-line I-O therapy naïve Part 3: Schedule finding of NKTR-214 in combination with nivolumab and ipilimumab. During this part of the study, the safety and tolerability, and efficacy of the triplet combination will be evaluated in approximately 30 treatment naïve patients with metastatic RCC or NSCLC to determine a RP2D and administration schedule. The first schedule to be evaluated Cohort A, is NKTR-214 0.006 mg/kg and nivolumab 360 mg q3w with the addition of ipilimumab 1 mg/kg q6w. Part 4: Dose expansion of NKTR-214 in combination with nivolumab and ipilimumab. Approximately 60 first line RCC or NSCLC patients (26-38 patients per indication) will be enrolled at the RP2D determined in Part 3 to further evaluate the safety, tolerability and efficacy of the triple combination. All patients enrolled in the study will be closely monitored to determine if there is response to the treatment as well as for any side effects that may occur. The efficacy of the combination will be assessed using objective response rate (ORR). Exploratory immunological biomarkers in plasma and tumour samples will evaluate immune activation.

View this trial on ClinicalTrials.gov

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Resources

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