A Study of the Effects of ALKS 4230 (Nemvaleukin Alfa) on Subjects With Solid Tumors

Phase 1

Completed

Conditions: Advanced Solid Tumors

Interventions: Drug: ALKS 4230
Drug: ALKS 4230 + pembrolizumab

Registration Number: NCT02799095

Lead Sponsor: Mural Oncology, Inc

Brief Summary: To better understand the safety and tolerability of ALKS 4230 in humans

Detailed Description: To investigate the safety and tolerability of ALKS 4230, determine the recommended Phase 2 dose (RP2D) and assess anti-tumor activity in Monotherapy and ALKS 4230 in Combination with pembrolizumab.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 243

Inclusion Criteria

For Part A, the subject has histological or cytological evidence of a solid tumor; for Part B, the subject has a diagnosis of melanoma or renal cell carcinoma
All subjects must have advanced solid tumors that have returned after treatment with established approved therapies or be intolerant of established therapies
Subjects enrolled in Part B or Part C must have at least 1 lesion that may qualify as a target lesion
Subject can move around on their own, has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and has an estimated life expectancy of at least 3 months
Subject must have adequate hematologic reserve
Subjects must have adequate liver function
Subjects must have adequate kidney function
Subjects must be recovered from the effects of any prior chemotherapy, immunotherapy, other prior systemic anticancer therapy, radiotherapy or surgery
Subjects who have received investigational agents must wait at least 4 weeks
Females of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and on Day 1 before the first dose is administered. A female not of childbearing potential is one who has undergone bilateral oophorectomies or who is postmenopausal, defined as >45 years of age and without a menstrual period for 12 consecutive months
Meets contraceptive requirements defined in the protocol
Additional criteria may apply

Exclusion Criteria

Subject is currently pregnant or breastfeeding, or is planning to become pregnant during the study
Subjects with an active infection or with a fever >/= 38.5 degrees C within 3 days of the first scheduled day of dosing for Cycle 1
Subjects with active or symptomatic central nervous system metastases are excluded. Subjects with central nervous system metastases are eligible for the study if the metastases have been treated by surgery and/or radiation therapy, the subject is off corticosteroids for at least 2 weeks and the subject is neurologically stable
Subjects have a mean QT interval corrected by the Fridericia Correction formula value of >470 msec (in females) or >450 msec (in males)
Subjects with known hypersensitivity to any components of ALKS 4230
Subjects with known hypersensitivity to any components of pembrolizumab (for patients in combination arm only)
Subjects who require pharmacologic doses of corticosteroids; replacement doses, topical, ophthalmologic, and inhalational steroids are permitted
Subjects who developed autoimmune disorders while on prior immunotherapy, including pneumonitis, nephritis, and neuropathy
Subjects with any other concurrent uncontrolled illness, including mental illness or substance abuse, which may interfere with the ability of the subject to cooperate and participate in the study
The subject is known to be positive for human immunodeficiency virus (HIV), hepatitis B or C, or active tuberculosis, or has a known history of tuberculosis
Subjects with dyspnea at rest of requiring oxygen therapy
Subjects active autoimmune disease requiring systemic treatment within the past 30 days
Subjects who received radiotherapy within the last 4 weeks before start of study treatment administration with the exception of limited field palliative radiotherapy
Subjects who have received systemic immunomodulatory agents within 28 days prior to C1D1.
Subjects who have received administration of a live, attenuated vaccine within 4 weeks of Cycle 1, Day1.
Prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow transplant recipients
Subjects who have received prior IL-2 based or IL-15 based cytokine therapy
Additional criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ALKS 4230	ALKS 4230	-
ALKS 4230 + pembrolizumab	ALKS 4230 + pembrolizumab	-

Primary Outcome Measures

Name	Time	Method
Part A: Number of Participants With Dose-limiting Toxicities (DLTs) Based on Common Terminology Criteria for Adverse Events (CTCAE)	Cycle 1 Day 1 through Cycle 2 Day 15 (Cycle 1 length = 14 days; Cycle 2 length= 21 days)	DLT was defined by any of following events possibly, probably, or definitely related to ALKS 4230: Grade 4 neutrophil count decreased (neutropenia); Febrile neutropenia; CTCAE Grade 4 thrombocytopenia; Thrombocytopenia; Any Grade 3 cardiac or central nervous system toxicity; Liver transaminase elevation higher than 8\upper limit of normal (ULN) or total bilirubin higher than 6\ULN; Grade 4 hypoalbuminemia; Fever more than (\>) 40 degree Celsius (°C) sustained for \>24 hours; Hypotension required the use of pressors or prolonged hospitalization (\>48 hours) for hypotension requiring medical intervention; Grade 3 or higher electrolyte abnormalities; Increase in amylase or lipase; Grade 3 or higher nausea, vomiting, or diarrhea; Any other Grade 4 nonhematologic toxicity or any other Grade 3 non-hematologic toxicity; Any other toxicity or adverse event (AE) not defined above that resulted in participant removal from the study or discontinuation of dosing by the Investigator.
Parts A, B, and C: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From first dose of study drug until 30 days after last dose (up to 10 months for Part A; up to 41.3 months for Part B; up to 51.5 months for Part C)	TEAEs were defined as AEs that were newly occurring or worsening from the time of the first dose of study drug. An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product.
Parts A, B, and C: Number of Participants With TEAEs by Severity Grading	From first dose of study drug until 30 days after last dose (up to 10 months for Part A; up to 41.3 months for Part B; up to 51.5 months for Part C)	TEAEs were defined as AEs that were newly occurring or worsening from the time of the first dose of study drug. Severity was graded according to the National Cancer Institute (NCI) CTCAE (version 4.03) where, Grade 1: Mild- asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate- minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. As planned, Grades 1 and 2 were combined for reporting.
Parts B and C: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1	From first dose of study drug up to 40.3 months for Part B and up to 50.5 months for Part C	ORR rate was defined as the percentage of participants with objective evidence of CR or PR based on RECIST v1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). Partial Response (PR): At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Name	Time	Method
Part B and Part C Cohorts C5, C6, C7: Durable Response Rate (DRR) Based on RECIST v.1.1	From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C	DRR was defined as the percentage of participants with an objective response (complete or partial response per RECIST 1.1) lasting continuously for 6 months and starting any time within 12 months of initiating the study drug.
Parts A, B, and C: Serum Concentrations of Nemvaleukin Alfa	Cycle 1 and 2 Day 1: 0, 0.5, 1, 2, 4, 8, 16, and 24 hours post-dose; Cycle 1 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, and 72 hours post-dose; Cycle 2 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, 72, and 240 hours post-dose	Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts.
Parts A, B and C: Area Under Concentration From Time Zero to the Last Quantifiable Concentration (AUClast) of Nemvaleukin Alfa	Cycle 1 and 2 Day 1: 0, 0.5, 1, 2, 4, 8, 16, and 24 hours post-dose; Cycle 1 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, and 72 hours post-dose; Cycle 2 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, 72, and 240 hours post-dose	Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts.
Parts A, B and C: Maximum Observed Serum Concentration (Cmax) of Nemvaleukin Alfa	Cycle 1 and 2 Day 1: 0, 0.5, 1, 2, 4, 8, 16, and 24 hours post-dose; Cycle 1 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, and 72 hours post-dose; Cycle 2 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, 72, and 240 hours post-dose	Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts.
Parts A, B and C: Time to Reach Cmax (Tmax) of Nemvaleukin Alfa	Cycle 1 and 2 Day 1: 0, 0.5, 1, 2, 4, 8, 16, and 24 hours post-dose; Cycle 1 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, and 72 hours post-dose; Cycle 2 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, 72, and 240 hours post-dose	Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts.
Parts A, B, and C: Proportion of Positive Anti-Nemvaleukin Alfa Antibodies (ADA)	From first dose of study drug up to 9 months (for Part A); up to 40.3 months (for Part B); up to 50.5 months (for Part C)	Overall proportion was calculated as: Number of participants (overall positive)/total number of participants in the cohort. Overall positive: Participants with at least 1 treatment-emergent ADA positive sample at any time during the treatment period.
Parts A, B, and C: Immune ORR (iORR) Based on Immune RECIST (iRECIST)	From first dose of study drug up to 9 months for Part A; up to 40.3 months for Part B; up to 50.5 months for Part C	iORR was defined as the percentage of participants with objective evidence of immune CR (iCR) or immune PR (iPR) based on iRECIST guidelines.
Parts A, B, and C: Disease Control Rate (DCR) Based on RECIST v.1.1	From first dose of study drug up to 9 months for Part A; up to 40.3 months for Part B; up to 50.5 months for Part C	Disease control rate was defined as the percentage of participants with objective evidence of CR, PR, or SD based on RECIST v.1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Parts A, B, and C: Immune DCR (iDCR) Based on iRECIST v1.1	From first dose of study drug up to 9 months for Part A; up to 40.3 months for Part B; up to 50.5 months for Part C	iDCR was defined as the percentage of participants with objective evidence of iCR, iPR (where iCR or iPR required confirmation), or immune stable disease (iSD) (where the iSD requires to occur at Cycle 4 or later).
Parts B, and C: Duration of Response (DOR) Based on RECIST v1.1	From the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause (up to 40.3 months for Part B and up to 50.5 months for Part C)	Duration of response was defined as the time from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Parts B, and C: Immune DOR (iDOR) Based on iRECIST	From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C	iDOR was defined as the time from the first documentation of response (iCR or iPR) to the first documentation of objective tumor progression (immune confirmed progressive disease \[iCPD\]) or death due to any cause based on iRECIST.
Part B and Part C Cohorts C5, C6, C7: Immune DRR (iDRR) Based on iRECIST	From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C	iDRR was defined as the percentage of participants with an objective response (complete or partial response per iRECIST) lasting continuously for 6 months and starting any time within 12 months of initiating the study drug.
Part B and Part C Cohorts C5, C6, C7: Progression-free Survival (PFS) Based on RECIST v.1.1	From first dose of study drug up to the first documentation of objective tumor progression or death due to any cause (up to 40.3 months for Part B and up to 50.5 months for Part C)	Progression-free survival was defined as the time from the first dose of nemvaleukin to the first documentation of objective tumor progression or death due to any cause. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Part B and Part C Cohorts C5, C6, C7: Immune PFS (iPFS)	From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C	iPFS was defined as the time from the first dose of study medication to the first documentation of objective tumor progression based on iRECIST (immune confirmed progressive disease \[iCPD\]) or death due to any cause.
Parts A, B and C: Maximum Cell Count of Whole Blood FoxP3+ T Cells (Tregs), Total Cluster of Differentiation (CD)8+ T Cells and Natural Killer (NK) Cells	Cycle 1 Day 1 (Cycle 1 length = 14 days for Part A and 21 days for Part B and C)
Parts A, B and C: Maximum Cell Count of Interferon-gamma (INF-γ) and Interleukin 6 (IL-6)	Cycle 1 Days 1 and 5; Cycle 2 Days 1 and 5 (Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts)

Trial Locations

Locations (3): Mural Oncology Investgational Site
🇦🇺
Albury, New South Wales, Australia
Mural Oncology Investigational Site
🇪🇸
Valencia, Spain
Alkermes Investigational Site
🇨🇦
Toronto, Ontario, Canada