Any Advanced Solid Tumors, Microsatellite Stable Colorectal Cancer, Non Small Cell Lung Cancer, Ovarian Cancer, Pancreatic Cancer, Small Cell Lung Cancer, Triple Negative Breast Cancer
Conditions
Keywords
NT-I7 (Efineptakin alfa), Solid Tumor, Pembrolizumab, Neoplasms, Lung, Breast, Pancreas, Colorectal, Non-small Cell Lung, Small Cell Lung, Thoracic Neoplasms, Interleukin 7, Carcinoma, Cancer, Programmed cell death protein (PD-1), Ovarian
Brief summary
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
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).
Interventions
DRUGNT-I7
Administered by intramuscular (IM) injection
DRUGpembrolizumab (KEYTRUDA®)
Administered by intravenous (IV) injection
Sponsors
NeoImmuneTech
Merck Sharp and Dohme LLC, Rahway, NJ, USA
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), Trial Treatment-related TEAEs and Trial Treatment-related SAEs | Up to 2 years and 3 months | A TEAE was any AE that starts on/after the first day of trial treatment or that worsens on/after the first day of trial treatment and up to 30 days (90 days for serious adverse events) after the date of last dose of trial drugs, or initiation of new anticancer therapy, whichever is earlier. A SAE was defined as any AE that resulted in any of the following outcomes: 1. Death; 2. A life-threatening AE; 3. An AE that resulted in inpatient hospitalization or prolongation of existing hospitalization for ≥24 hours; 4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; 5. A congenital anomaly/birth defect; 6. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. |
| Phase 1b: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) | Up to 21 days | A DLT was defined as any AE occurring within the first 21 days that was considered to be related to the trial treatments (NT-I7 and/or pembrolizumab) per the investigator, and that met at least one of the non-hematologic or hematologic criteria: * Grade 4 non-hematologic toxicity * Grade ≥ 3 diarrhea, nausea and vomiting * Grade ≥ 3 rash for ≥ 5 days * Grade 4 neutropenia for ≥ 5 days * Febrile neutropenia Grade 3 or Grade 4 * Other Grade 4 hematologic toxicity for ≥7 days, except thrombocytopenia * Any non-hematologic AE ≥ Grade 3 in severity * Any Grade 3 or Grade 4 non-hematologic laboratory value if medical intervention was required, led to hospitalization, persisted for \> 1 week, resulted in potential drug-induced liver injury * Other Grade ≥ 3 clinical laboratory abnormalities not reversible to ≤ Grade 1 within 72 hours * Prolonged delay in initiating Cycle 2 * Any treatment-related toxicity that caused treatment discontinuation in Cycle 1 * Grade 5 toxicity. |
| Phase 2a (Arms I to Va): Objective Response Rate (ORR) | Up to 2 years | ORR was defined as the percentage of participants who had at least one confirmed partial response (PR) or complete response (CR), per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1) and immune RECIST (iRECIST) as determined by the investigator. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Biomarker Cohort: Percentage of Area Occupied by Tumor-Infiltrating Lymphocytes (TILs) | Pre-treatment and post-treatment (maximum duration of treatment of approximately 2 years) | CD8 positivity TILs in tumor biopsy samples were identified using a validated immunohistochemistry (IHC) assay and certified by a pathologist. The percentage of area occupied by TILs was evaluated in the stroma area, tumor area and tumor - relevant tissue area both pre- and post-treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biomarker Cohort: ORR | Up to 2 years | ORR was defined as the percentage of participants who had at least one confirmed PR or CR, per RECIST v1.1 and iRECIST as determined by the investigator. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 1b/2a: Duration of Objective Response (DOR) | Up to 2 years | DOR was defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause, whichever occurs first, per RECIST 1.1 and iRECIST as determined by the investigator. |
| Phase 1b/2a: Disease Control Rate (DCR) | Up to 2 years | DCR was defined as the proportion of participants with a best overall response of CR, PR, stable disease (SD) per RECIST 1.1 and iRECIST as determined by the investigator.. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) at least a 20% increase in the sum of the diameters of target lesions), taking as reference the smallest sum diameters while on study. |
| Phase 1b/2a: Progression Free Survival (PFS) | Up to 2 years | PFS was defined as the time from the first trial treatment (Cycle 1, Day 1) to the first occurrence of progression or death from any cause, whichever occurs first per RECIST 1.1 and iRECIST as determined by the investigator. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, using the smallest sum observed on study as reference, with an absolute increase of at least 5 mm, or the appearance of new lesions, or unequivocal progression of non-target lesions, per RECIST 1.1. |
| Phase 1b/2a: Overall Survival (OS) | Up to 2 years | OS was defined as the time from first trial treatment (Cycle 1, Day 1) to death from any cause. |
| Phase 1b/2a: Number of Participants Who Experienced an Increase in Anti-Drug Antibodies (ADAs) to NT-I7 | Up to 2 years | Immunogenicity to NT-I7 was measured using a risk-based, tiered testing approach. This included screening and confirmatory assays for binding ADAs, epitope-specific assays to characterize ADA reactivity to whole NT-I7 vs IL-7 domain, and a cell-based neutralizing ADA assay for IL7 bioactivity. Participants' samples were obtained at baseline and over the course of treatment (to evaluate the prevalence and incidence of treatment-emergent/boosted ADA). Not detected or detected but not confirmed ADA was defined as negative. Detected and confirmed ADA was defined as positive. |
| Biomarker Cohort: Number of Participants Who Experienced TEAEs, SAEs, Trial Treatment-related TEAEs and Trial Treatment-related SAEs | Up to 2 years and 3 months | A TEAE was any AE that starts on/after the first day of trial treatment or that worsens on/after the first day of trial treatment and up to 30 days (90 days for serious adverse events) after the date of last dose of trial drugs, or initiation of new anticancer therapy, whichever is earlier. A SAE was defined as any AE that resulted in any of the following outcomes: Death; A life-threatening AE; An AE that resulted in inpatient hospitalization or prolongation of existing hospitalization for ≥24 hours; A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; A congenital anomaly/birth defect; Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. |
Countries
United States
Participant flow
Recruitment details
A total of 215 participants were enrolled in the United States from June 2020 to January 2025.
Pre-assignment details
The trial consisted of a dose escalation phase (Phase 1b) followed by a dose expansion phase (Phase 2a) and a Biomarker Cohort.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 131 Participants |
| Age, Continuous | 60.8 years STANDARD_DEVIATION 11.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 6 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized Unknown | 7 Participants |
| Race/Ethnicity, Customized White | 158 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 3 | 1 / 6 | 9 / 16 | 20 / 34 | 12 / 17 | 19 / 29 | 16 / 28 | 18 / 32 | 24 / 34 | 8 / 13 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 16 / 16 | 34 / 34 | 17 / 17 | 29 / 29 | 27 / 28 | 32 / 32 | 34 / 34 | 13 / 13 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 1 / 6 | 4 / 16 | 28 / 34 | 11 / 17 | 15 / 29 | 20 / 28 | 18 / 32 | 27 / 34 | 9 / 13 |
Outcome results
None listed