NT-I7 (Efineptakin Alfa) in Combination With Pembrolizumab in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The main purposes of Phase 1b of this study are to determine the following in participants with advanced solid tumors: Safety and tolerability of NT-I7 in combination with pembrolizumab Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) The main purpose of Phase 2a of this study is to assess the preliminary anti-tumor activity of NT-I7 in combination with pembrolizumab in participants with checkpoint inhibitor (CPI) treated and naïve relapsed and refractory (R/R) tumors. The main purpose of the Biomarker Cohort is to assess a potential correlation between tumor infiltrating lymphocytes (TILs) and clinical benefits in participants with CPI-naïve R/R ovarian cancer (OC).

Detailed Description
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This is a multicenter, open-label Phase 1b/2a study of NT-I7 in combination with pembrolizumab. The study consists of a dose escalation phase (Phase 1b) followed by a dose expansion phase (Phase 2a) and a Biomarker Cohort. The Phase 1b is designed to assess the safety and tolerability, including determination of the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7. The main purpose of Phase 2a of this study is to assess the preliminary antitumor activity of NT-I7 in combination with pembrolizumab in participants with relapsed/refractory checkpoint inhibitor (CPI)-treated Triple Negative Breast Cancer (TNBC), Non-small Cell Lung Cancer (NSCLC), and Small Cell Lung Cancer (SCLC) checkpoint inhibitor (CPI)-naïve Microsatellite Stable Colorectal Cancer (MSS-CRC), and Pancreatic Cancer (PC) The Biomarker Cohort is designed to assess the correlation between tumor infiltrating lymphocytes (TILs) and clinical benefits of NT-I7 in combination with pembrolizumab in participants with CPI naïve R/R Ovarian Cancer (OC).

Official Title
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An Open-label Phase 1b/2a Study of NT-I7 (Efineptakin Alfa) in Combination With Pembrolizumab in Subjects With Relapsed/Refractory Advanced Solid Tumors

Conditions
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Ovarian Cancer, Any Advanced Solid Tumors, Triple Negative Breast Cancer, Non Small Cell Lung Cancer, Small Cell Lung Cancer, Microsatellite Stable Colorectal Cancer, Pancreatic Cancer

Intervention / Treatment
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* Drug: NT-I7
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (Participants must meet all the following to be eligible) Participants with histologically or cytologically confirmed advanced or metastatic solid tumors. Have measurable disease per RECIST v1.1. Participants enrolling in the Phase 1b, Arms I, IV, IVa, V, and Va of the Phase 2a, and the Biomarker Cohort OC must have biopsiable disease. Female participants who are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks; female participants of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use dual methods of contraception for the duration of study treatment and for 120 days after the last dose of study treatment (pembrolizumab and/or NT-I7). Non-sterile male participants who are sexually active with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use highly effective method(s) of contraception for the duration of study treatment and for 120 days after the last dose of study treatment (pembrolizumab and/or NT-I7). Meet the requirements for the intended stages and arms (disease specific inclusion criteria), as follows: Applicable to the Dose escalation phase (Phase 1b) only: (Biopsy Arm) Relapsed/refractory advanced solid tumors. Applicable to the Dose expansion phase (Phase 2a) only: Anti-PD-1/anti-PD-L1 refractory criteria for CPI-treated TNBC, NSCLC, and SCLC Has received at least 2 doses of an approved anti-PD-1/anti-PD-L1 monoclonal antibody (mAb). Has demonstrated disease progression after anti-PD-1/anti-PD-L1. Specific to Arm I: CPI-treated R/R TNBC (Biopsy Arm) Histopathologic or cytologic documented TNBC. Received one or more prior therapies for TNBC in the advanced or metastatic setting, and prior treatment (for advanced, metastatic or (neo) adjuvant). Specific to Arm II: CPI-treated R/R NSCLC Had prior treatment with CPI. Participants with estimated glomerular filtration rate (EGFR), BRAF, or c-ros oncogene 1(ROS1) mutations or anaplastic lymphoma kinase (ALK) translocations are required to have received prior therapy with the appropriate tyrosine kinase inhibitor (TKI). Specific to Arm III: CPI-treated R/R SCLC Recurrent extensive-stage SCLC; Received prior CPI therapy. Specific to Arm IV and IVa: CPI-naïve R/R MSS-CRC (Biopsy Arm) MSS-CRC (categorized as MSS by immunohistochemistry(IHC) or polymerase chain reaction (PCR). Previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan; participants treated with CPI are not eligible. Specific to Arm V and Va: CPI-naïve R/R Pancreatic Cancer (Biopsy Arm) Have documented radiographic progression to or documented in tolerance of first line systemic chemotherapy which included either gemcitabine or Fluorouracil (5-FU)-based regimen (including capecitabine); participants treated previously with CPI are not eligible. Specific to Biomarker Cohort: CPI-naïve R/R Ovarian Cancer Up to 5 prior lines of treatment, including platinum-based treatment(s); participants treated previously with CPIs are not eligible. Willing to provide pre- and on-treatment tumor biopsies. Exclusion Criteria: Pregnant, lactating or breastfeeding. Receiving chemotherapy or any anti-cancer therapy (approved or investigational) with half-life <1 week within 30 days or 5 half-lives. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate if stable. Participants who have received treatment with systemic immunosuppressive medications. Has a history of non-infectious pneumonitis that required steroids or current pneumonitis. Has had an allogenic tissue/solid organ transplant or bone marrow transplant. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137) and was discontinued from that treatment due to a Grade 3 or higher Immune related adverse event (irAE).

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: NT-I7 Dose Escalation<br>NT-I7 will be administered on Day 1 of alternate 21 day cycles (Cycle 1, 3, 5 etc.). Dosage will increase until the maximum tolerated dose (MTD) and/or the recommended phase 2 (RP2D) dose is reached. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Treated Triple Negative Breast Cancer<br>Participants with checkpoint inhibitor (CPI) treated relapsed or refractory triple negative breast cancer (TNBC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Treated Non-small Cell Lung Cancer<br>Participants with checkpoint inhibitor (CPI) treated relapsed or refractory non-small cell lung cancer (NSCLC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Treated Small Cell Lung Cancer<br>Participants with checkpoint inhibitor (CPI) treated relapsed or refractory small cell lung cancer (SCLC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Naïve Microsatellite Stable Colorectal Cancer<br>Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory microsatellite stable colorectal cancer (MSS-CRC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Naïve Pancreatic Cancer<br>Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory pancreatic cancer (PC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Naïve Microsatellite Stable Colorectal Cancer, Expansion Cohort<br>Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory microsatellite stable colorectal cancer (MSS-CRC). Participants will receive 1200 µg/kg of NT-I7 and and a fixed dose of 200 mg of pemprolizumab. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Phase 2a: CPI Naïve Pancreatic Cancer, Expansion Cohort<br>Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory pancreatic cancer (PC).Participants will receive 1200 µg/kg of NT-I7 and a fixed dose of 200 mg of pemprolizumab. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|
| Experimental: Biomarker Cohort: CPI Naïve Ovarian Cancer<br>Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory ovarian cancer (OC). Participants will receive a starting dose of 960 µg/kg of NT-I7 and a fixed dose of 200 mg of pemprolizumab. Pembrolizumab will be administered on Day 1 of every 21 day cycle. | Drug: NT-I7<br>* Administered by intramuscular (IM) injection<br>* Other names: rhIL-7-hyFc;Drug: Pembrolizumab<br>* Administered by intravenous (IV) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Safety and Tolerability of NT-I7 in Combination With Pembrolizumab to Determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7 | Incidence, nature and severity of Adverse Events (AEs) graded according to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 Incidence and nature of Dose-Limiting Toxicities (DLTs) | Up to 2 years | 
| Phase 1b: Safety and Tolerability of NT-I7 in Combination With Pembrolizumab to Determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7 | Statistical correlation of dose levels with safety and efficacy parameters. | Up to 2 years | 
| Phase 2a: Preliminary Assessment of the Objective Response Rate (ORR) of NT-I7 in Combination with Pembrolizumab |  | Up to 2 years | 
| Biomarker Cohort: Number of Tumor-Infiltrating Lymphocytes (TILs) |  | Up to 2 years | 
| Biomarker Cohort: Distribution of Tumor-Infiltrating Lymphocytes (TILs) | TILs in tumor biopsy samples will be identified using a multi-spectral Immunofluorescence (IF) assay. | Up to 2 years | 
| Biomarker Cohort: Phenotype of Tumor-Infiltrating Lymphocytes (TILs) | TILs in tumor biopsy samples will be identified using a multi-spectral Immunofluorescence (IF) assay. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Objective Response (DOR) |  | Up to 2 years | 
| Disease Control Rate (DCR) |  | Up to 2 years | 
| Progression Free Survival (PFS) |  | Up to 2 years | 
| Overall Survival (OS) |  | Up to 2 years | 
| Number of Participants Who Experience an Increase in Anti-Drug Antibodies (ADAs) to NT-I7 |  | Up to 2 years | 
| Biomarker Cohort: Objective Response Rate (ORR) |  | Up to 2 years | 
| Incidence, Nature, and Severity of Adverse Events (AEs) graded according to National Cancer Institute Common Terminologies Criteria for Adverse Events (NCI CTCAE) v5.0 |  | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pembrolizumab, Neoplasms, Lung, Breast, Pancreas, Ovarian, NT-I7 (Efineptakin alfa), Solid Tumor, Colorectal, Non-small Cell Lung, Small Cell Lung, Thoracic Neoplasms, Interleukin 7, Carcinoma, Cancer, Programmed cell death protein (PD-1)