Study of NKTR 255 in Combination With Cetuximab in Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1b/2, open-label multicenter study evaluating NKTR-255 as a monotherapy and together with cetuximab in patients with head and neck squamous cell carcinoma (HNSCC), colorectal carcinoma (CRC), cutaneous squamous cell carcinoma (cSCC), anal cell carcinoma (ASCC) and cervical cancer. The recommended phase 2 dose of NKTR-255, determined in the dose escalation phase (Phase 1b), will be used to treat patients in Phase 2 of this study.

Detailed Description
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NKTR-255 is a cytokine that is designed to regulate T and natural killer cell activation, proliferation and promote their anti-tumor effects. In the dose escalation (Phase 1/b) phase patients with HNSCC or CRC will be treated with ascending doses of NKTR-255 in combination with cetuximab, until the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) is reached. The recommended phase 2 dose of NKTR-255 will be used to treat patients in Phase 2 of this study. In the dose expansion phase (Phase 2), patients will be treated with NKTR-255 alone and together with cetuximab as follows: Cohort A - HNSCC; Cohort B - CRC; Cohort C - cSCC; Cohort D - ASCC; Cohort E - Cervical Cancer. Patients who achieve optimal response will be given the option to continue treatment with NKTR-255 as single agent for maintenance.

Official Title
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A Phase 1b/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-255 Monotherapy or in Combination With Cetuximab as a Salvage Regimen for Solid Tumors

Conditions
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Head and Neck Squamous Cell Carcinoma, Colorectal Cancer, Cutaneous Squamous Cell Carcinoma, Anal Squamous Cell Carcinoma, Cervical Cancer

Intervention / Treatment
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* Drug: NKTR-255
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed diagnosis of a locally advanced or metastatic HNSCC, CRC, cSCC, ASCC, or cervical cancer. Life expectancy > 12 weeks as determined by the Investigator. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Measurable disease per RECIST 1.1. HNSCC: Progression on any first or second line platinum-based chemotherapy and/or anti-PD-1 or programmed death-ligand 1 antibody. CRC: Patients must have received or were intolerant to at least 2 prior cancer therapy regimens administered for metastatic disease. cSCC Patients must have received prior therapy including anti-PD-1 and platinum-based chemotherapy, have documented platinum-refractory disease, or be ineligible/unfit for platinum-based therapy. aSCC Patients must have received prior therapy including anti-PD-1 and platinum-based chemotherapy, have documented platinum-refractory disease, or be ineligible/unfit for platinum-based therapy. If human immunodeficiency virus (HIV)-positive, patients must also have CD4+ count ≥ 300/μL, undetectable viral load, and be receiving highly active antiretroviral therapy at the time of screening. Cervical Cancer Patients must have experienced progression (or toxicity precluding additional treatment) on any first- or second-line platinum-based chemotherapy and anti-PD-(L)1, have documented platinum-refractory disease, or be ineligible/unfit for platinum-based therapy. Patients must have known status by pathology for HPV Key Exclusion Criteria: Use of an investigational agent or an investigational device within 28 days before administration of first dose of study drug(s) Prior surgery or radiotherapy within 14 days of initiating study drug(s) Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis; active infection requiring systemic therapy within 7 days prior to dosing Patients who have been previously treated with IL-2 or IL-15 Known Grade 3 or 4 hypersensitivity reaction to cetuximab, history of allergy to red meat or tick bites, or history of positive test results for immunoglobulin E antibodies against cetuximab Patients who have an active, known, or suspected autoimmune disease NOTE: Other protocol defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1: Dose escalation cohorts will be sequential Phase 2: Cohorts A and B will be in parallel
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation of NKTR-255 with Cetuximab<br>Establish RP2D, of NKTR-255 with cetuximab. | Drug: NKTR-255<br>* NKTR-255 IV every 21 days<br>Drug: Cetuximab<br>* Cetuximab will be given at specified doses on specified days<br>* Other names: Erbitux®;|
| Experimental: Dose Expansion of NKTR-255 with Cetuximab - Cohort A<br>The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with HNSCC. | Drug: NKTR-255<br>* NKTR-255 IV every 21 days<br>Drug: Cetuximab<br>* Cetuximab will be given at specified doses on specified days<br>* Other names: Erbitux®;|
| Experimental: Dose Expansion of NKTR-255 with Cetuximab - Cohort B<br>The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with CRC. | Drug: NKTR-255<br>* NKTR-255 IV every 21 days<br>Drug: Cetuximab<br>* Cetuximab will be given at specified doses on specified days<br>* Other names: Erbitux®;|
| Experimental: Dose Expansion of NKTR-255 with Cetuximab - Cohort C<br>The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with cSCC. | Drug: NKTR-255<br>* NKTR-255 IV every 21 days<br>Drug: Cetuximab<br>* Cetuximab will be given at specified doses on specified days<br>* Other names: Erbitux®;|
| Experimental: Dose Expansion of NKTR-255 with Cetuximab - Cohort D<br>The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with ASCC. | Drug: NKTR-255<br>* NKTR-255 IV every 21 days<br>Drug: Cetuximab<br>* Cetuximab will be given at specified doses on specified days<br>* Other names: Erbitux®;|
| Experimental: Dose Expansion of NKTR-255 with Cetuximab - Cohort E<br>The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with cervical cancer. | Drug: NKTR-255<br>* NKTR-255 IV every 21 days<br>Drug: Cetuximab<br>* Cetuximab will be given at specified doses on specified days<br>* Other names: Erbitux®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) of NKTR-255 in combination with Cetuximab in R/R HNSCC or CRC for Phase 1b Dose Escalation | Safety and tolerability of NKTR-255 in combination with cetuximab as evaluated by dose limiting toxicities, incidence of drug-related Adverse Events (AEs), SAEs, and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE 5.0 | 60 days after the last dose of study treatment. | 
| Incidence of Treatment-Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) of NKTR-255 monotherapy and in combination with Cetuximab in R/R HNSCC, CRC, cSCC, ASCC, and cervical cancer for Phase 2 Dose Expansion | Safety and tolerability of NKTR-255 in combination with cetuximab as evaluated by dose limiting toxicities, incidence of drug-related Adverse Events (AEs), SAEs, and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE 5.0 | Through study completion, an expected average of 1 year | 
| The maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) or NKTR-255 in combination with cetuximab in R/R HNSCC or CRC for Phase 1b Dose Escalation | To define the MTD and/or RP2D of NKTR-255 in combination with cetuximab | Through study completion, an expected average of 1 year | 
| Objective Response Rate (ORR) by RECIST 1.1 of NKTR-255 in combination with Cetuximab in R/R metastatic HNSCC or CRC for Phase 2 Dose Expansion | ORR is defined as the proportion of enrolled participants who achieved a Best Overall Response (BOR) of CR or PR. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR is calculated as the sum of CR and PR. | Through study completion, an expected average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR by RECIST 1.1 of NKTR-255 monotherapy in R/R cSCC, ASCC, and cervical cancer | ORR is defined as the proportion of enrolled participants who achieved a Best Overall Response (BOR) of CR or PR. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR is calculated as the sum of CR and PR. | Through study completion, an expected average of 1 year | 
| Overall Survival (OS) of NKTR-255 monotherapy and in combination with Cetuximab | OS is defined as the time from date of first dose to the date of death. | Through study completion, an expected average of 1 year | 
| Progression-Free Survival (PFS) of NKTR-255 monotherapy and in combination with Cetuximab | PFS is defined as the time from date of first dose to the date of the first objectively documented tumor progression or death due to any cause | Through study completion, an expected average of 1 year | 
| Change from baseline in immune cell populations (natural killer NK], CD8+ cells, and other immune populations) after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy |  | Through study completion, an expected average of 1 year | 
| Change in tumor cells levels after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy |  | Through study completion, an expected average of 1 year | 
| Change in cytokine levels after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy |  | Through study completion, an expected average of 1 year | 
| Changes in gene expression after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy |  | Through study completion, an expected average of 1 year | 
| Maximum Plasma Concentration (Cmax) for NKTR-255 and cetuximab |  | Through study completion, an expected average of 1 year | 
| Area under the concentration-time curve (AUC) for NKTR-255 and cetuximab |  | Through study completion, an expected average of 1 year | 
| Clearance (CL) for NKTR-255 and cetuximab |  | Through study completion, an expected average of 1 year | 
| Volume of Distribution of NKTR-255 and cetuximab |  | Through study completion, an expected average of 1 year | 
| Half-life of NKTR-255 and cetuximab |  | Through study completion, an expected average of 1 year | 
| The development of anti-drug antibodies (ADA) against NKTR-255 and cetuximab | The timing of appearance of anti-NKTR-255 and anti-cetuximab antibodies will be examined. | Through study completion, an expected average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HNSCC, Head and Neck Squamous Cell Carcinoma, CRC, Colorectal Cancer, cSCC, Cutaneous Squamous Cell Carcinoma, ASCC, Anal Squamous Cell Carcinoma, Cervical Cancer, NKTR-255, Cetuximab, Erbitux®