Study of NKTR 255 in Combination With Cetuximab in Solid Tumors

Phase 1

Completed

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

Interventions: Drug: NKTR-255
Drug: Cetuximab

Registration Number: NCT04616196

Lead Sponsor: Nektar Therapeutics

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Expansion of NKTR-255 with Cetuximab - Cohort B	NKTR-255	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with CRC.
Dose Expansion of NKTR-255 with Cetuximab - Cohort C	NKTR-255	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with cSCC.
Dose Escalation of NKTR-255 with Cetuximab	NKTR-255	Establish RP2D, of NKTR-255 with cetuximab.
Dose Expansion of NKTR-255 with Cetuximab - Cohort C	Cetuximab	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with cSCC.
Dose Expansion of NKTR-255 with Cetuximab - Cohort E	NKTR-255	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with cervical cancer.
Dose Expansion of NKTR-255 with Cetuximab - Cohort D	NKTR-255	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with ASCC.
Dose Expansion of NKTR-255 with Cetuximab - Cohort E	Cetuximab	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with cervical cancer.
Dose Expansion of NKTR-255 with Cetuximab - Cohort A	NKTR-255	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with HNSCC.
Dose Escalation of NKTR-255 with Cetuximab	Cetuximab	Establish RP2D, of NKTR-255 with cetuximab.
Dose Expansion of NKTR-255 with Cetuximab - Cohort A	Cetuximab	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with HNSCC.
Dose Expansion of NKTR-255 with Cetuximab - Cohort B	Cetuximab	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with CRC.
Dose Expansion of NKTR-255 with Cetuximab - Cohort D	Cetuximab	The RP2D of NKTR-255 will be evaluated as monotherapy and in combination with cetuximab in patients with ASCC.

Primary Outcome Measures

Name	Time	Method
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	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
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	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
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	Through study completion, an expected average of 1 year	To define the MTD and/or RP2D of NKTR-255 in combination with cetuximab
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	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

Name	Time	Method
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
Overall Survival (OS) of NKTR-255 monotherapy and in combination with Cetuximab	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.
Progression-Free Survival (PFS) of NKTR-255 monotherapy and in combination with Cetuximab	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
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
Area under the concentration-time curve (AUC) 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
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
ORR by RECIST 1.1 of NKTR-255 monotherapy in R/R cSCC, ASCC, and cervical cancer	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.
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
Clearance (CL) for 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	Through study completion, an expected average of 1 year	The timing of appearance of anti-NKTR-255 and anti-cetuximab antibodies will be examined.
Maximum Plasma Concentration (Cmax) for NKTR-255 and cetuximab	Through study completion, an expected average of 1 year

Trial Locations

Locations (6): University of California, San Diego
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San Diego, California, United States
START Center for Cancer Care
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San Antonio, Texas, United States
Mary Crowley Cancer Research
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Dallas, Texas, United States
MD Anderson Cancer Center
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Houston, Texas, United States
University of Minnesota
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Minneapolis, Minnesota, United States
University of California, San Francisco
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San Francisco, California, United States