Study of NKTR 255 in Combination With Cetuximab in Solid Tumors

• ClinicalTrials.gov Identifier: NCT04616196
• Recruitment Status: Active, not recruiting
• First Posted: November 4, 2020
• Last Update Posted: March 17, 2023
• Sponsor: Nektar Therapeutics
• Information provided by (Responsible Party): Nektar Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Head and Neck Squamous Cell Carcinoma; Colorectal Cancer; Cutaneous Squamous Cell Carcinoma; Anal Squamous Cell Carcinoma; Cervical Cancer	Drug: NKTR-255; Drug: Cetuximab	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 326 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Phase 1: Dose escalation cohorts will be sequential Phase 2: Cohorts A and B will be in parallel
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 30, 2020
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: August 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 60 days after the last dose of study treatment. ]
   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
2. 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 [ Time Frame: Through study completion, an expected average of 1 year ]
   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
3. 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 [ Time Frame: Through study completion, an expected average of 1 year ]
   To define the MTD and/or RP2D of NKTR-255 in combination with cetuximab
4. 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 [ Time Frame: Through study completion, an expected average of 1 year ]
   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.

Secondary Outcome Measures :

1. ORR by RECIST 1.1 of NKTR-255 monotherapy in R/R cSCC, ASCC, and cervical cancer [ Time Frame: Through study completion, an expected average of 1 year ]
   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.
2. Overall Survival (OS) of NKTR-255 monotherapy and in combination with Cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
   OS is defined as the time from date of first dose to the date of death.
3. Progression-Free Survival (PFS) of NKTR-255 monotherapy and in combination with Cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
   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
4. 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 [ Time Frame: Through study completion, an expected average of 1 year ]
5. Change in tumor cells levels after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy [ Time Frame: Through study completion, an expected average of 1 year ]
6. Change in cytokine levels after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy [ Time Frame: Through study completion, an expected average of 1 year ]
7. Changes in gene expression after administration of NKTR-255 in combination with cetuximab and NKTR-255 monotherapy [ Time Frame: Through study completion, an expected average of 1 year ]
8. Maximum Plasma Concentration (Cmax) for NKTR-255 and cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
9. Area under the concentration-time curve (AUC) for NKTR-255 and cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
10. Clearance (CL) for NKTR-255 and cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
11. Volume of Distribution of NKTR-255 and cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
12. Half-life of NKTR-255 and cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
13. The development of anti-drug antibodies (ADA) against NKTR-255 and cetuximab [ Time Frame: Through study completion, an expected average of 1 year ]
    The timing of appearance of anti-NKTR-255 and anti-cetuximab antibodies will be examined.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

University of California, San Diego

San Diego, California, United States, 92103

University of California, San Francisco

San Francisco, California, United States, 94158

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Texas

Mary Crowley Cancer Research

Dallas, Texas, United States, 75230

MD Anderson Cancer Center

Houston, Texas, United States, 77030

START Center for Cancer Care

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Nektar Therapeutics

Investigators

• Study Director: Study Director; Nektar Therapeutics

More Information

• Responsible Party: Nektar Therapeutics
• ClinicalTrials.gov Identifier: NCT04616196
• Other Study ID Numbers: 19-255-03
• First Posted: November 4, 2020
• Last Update Posted: March 17, 2023
• Last Verified: March 2023

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

Keywords provided by Nektar Therapeutics:

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®

Additional relevant MeSH terms:

Carcinoma; Colorectal Neoplasms; Carcinoma, Squamous Cell; Uterine Cervical Neoplasms; Squamous Cell Carcinoma of Head and Neck; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplasms, Squamous Cell; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Head and Neck Neoplasms; Cetuximab; Antineoplastic Agents, Immunological; Antineoplastic Agents