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

Mural Oncology, Inc243 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

243

Conditions

Advanced Solid Tumors

Interventions

ALKS 4230DRUG

Intravenous (IV) infusion over 30 minutes given daily for 5 consecutive days followed by an off-treatment period

ALKS 4230 + pembrolizumabDRUG

IV infusion of ALKS 4230 over 30 minutes given daily for 5 consecutive days followed by an off-treatment period; pembrolizumab administered IV once with ALKS 4230 on the first day of each cycle

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (31)

Outcomes

Primary Outcomes

Part A: Number of Participants With Dose-limiting Toxicities (DLTs) Based on Common Terminology Criteria for Adverse Events (CTCAE)

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.

Time frame: Cycle 1 Day 1 through Cycle 2 Day 15 (Cycle 1 length = 14 days; Cycle 2 length= 21 days)

Parts A, B, and C: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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.

Time frame: 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)

Parts A, B, and C: Number of Participants With TEAEs by Severity Grading

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Parts A, B, and C: Serum Concentrations of Nemvaleukin Alfa

Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts.

Time frame: 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

Parts A, B and C: Area Under Concentration From Time Zero to the Last Quantifiable Concentration (AUClast) of Nemvaleukin Alfa

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 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 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)

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.

Time frame: 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)

Parts A, B, and C: Immune ORR (iORR) Based on Immune RECIST (iRECIST)

iORR was defined as the percentage of participants with objective evidence of immune CR (iCR) or immune PR (iPR) based on iRECIST guidelines.

Time frame: 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

Parts A, B, and C: Disease Control Rate (DCR) Based on RECIST v.1.1

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.

Time frame: 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

Parts A, B, and C: Immune DCR (iDCR) Based on iRECIST v1.1

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).

Time frame: 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

Parts B, and C: Duration of Response (DOR) Based on RECIST v1.1

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.

Time frame: 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)

Parts B, and C: Immune DOR (iDOR) Based on iRECIST

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.

Time frame: From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Part B and Part C Cohorts C5, C6, C7: Durable Response Rate (DRR) Based on RECIST v.1.1

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.

Time frame: From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Part B and Part C Cohorts C5, C6, C7: Immune DRR (iDRR) Based on iRECIST

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.

Time frame: From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Part B and Part C Cohorts C5, C6, C7: Progression-free Survival (PFS) Based on RECIST v.1.1

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.

Time frame: 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)

Part B and Part C Cohorts C5, C6, C7: Immune PFS (iPFS)

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.

Time frame: From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

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

Time frame: 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)

Time frame: 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)