A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12) (JAVELIN IL-12)

NCT02994953 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: MS201781_00312017-002212-13
• Study Type: interventional
• Target: 52
• Locations: 7 countries
• Sites: 33

Brief Summary

The study consisted of 2 parts: Dose Escalation phase (Part A) and Expansion phase (Part B). The dose escalation phase evaluated the safety, tolerability, and PK of avelumab in combination with M9241 in subjects with locally advanced, unresectable, or metastatic solid tumors. Expansion phase assessed the safety and clinical activity of the combination regimen in selected tumor types. In Expansion phase subjects who had completed the combination treatment of avelumab at a given dose level of M9241, a safety review was performed by the Safety monitoring committee in order to make a decision on the next dose level. Successive cohorts of 3 to 6 subjects were treated with escalating doses of M9241 with avelumab intravenous (IV).

Conditions

Advanced Solid Tumors

Keywords

Avelumab; M9241; NHS-IL12; Advanced Solid Tumors

Outcome Measures

Primary Outcomes (6)

• Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03

  An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.

  From first dose of study treatment up to 1311 days

• Part B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03

  An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.

  Part B: From first dose of study treatment up to 443 days

• Part A: Number of Participants With Treatment-Related Adverse Events (TRAEs) by Severity Based on Grade 3,4 and 5 According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

  AE was any untoward medical occurrence in a participants who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with Grade 3,4 and 5 by severity were only reported.

  From first dose of study treatment up to 1311 days

• Part B: Number of Participants With Treatment-Related Adverse Events (TRAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

  AE was any untoward medical occurrence in a participants who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs and TRAEs by severity were reported.

  First dose of study drug up to 443 days

• Part A: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)

  A DLT is any Grade (\>=) 3 non-hematologic AE or any Grade (\>=) 4 hematologic AE according to the NCI-CTCAE v4.03, occurring during the DLT observation period that is related to either or both study drugs as determined by the Investigator or Sponsor at any dose and judged not to be related to the underlying disease or any previous or concomitant medication. The following are exceptions to the DLTs: Grade \>=3 thrombocytopenia with medically concerning bleeding; Any Grade 3 autoimmune thyroid-related toxicity that doesn't clinically resolve to \<= Grade 2 within 7 days of initiating therapy will be a DLT. Any Grade 4 neutropenia of \< 5 days duration; Grade 3 infusion-related reaction resolving within 6 hours of infusion; Grade 3 diarrhea or skin toxicity that resolves to Grade \<= 1 within 7 days after medical management; Transient Grade 3 fatigue, local reactions, flu-like symptoms; Tumor flare phenomenon of known or suspected tumor did not consider a DLT.

  Time from first treatment to final assessment up to 3 weeks

• Part B: Number of Participants With Confirmed Best Overall Response (BOR) Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  Confirmed BOR was defined as the best response of any of the confirmed complete response (CR), confirmed partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference).CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Not evaluable (NE): No post-baseline assessment. BOR assessments were assessed by investigators.

  First dose of study drug up to 443 days

Secondary Outcomes (27)

• Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of Avelumab

  Predose (PrD),1,4,8 hours postdose (PD) on Day 1,22 of Cycle 1 & 2; PrD,1 hour PD on Day 8,15 of Cycle 1 & Day 8,15,22 of Cycle 2; PrD, 1 hour PD on Day 1 Cycle 3 & Day 1,15 of Cycle 4; PrD on Day 1 of Cycle 7,10,13,16,19,22,25, & 28 (Each cycle: 28 days)

• Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab

  PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)

• Part A: Terminal Elimination Rate Constant (Lambdaz) of Avelumab

  PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)

• Part A: Maximum Observed Serum Concentration (Cmax) of Avelumab

  PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)

• Part A: Minimum Observed Serum Concentration (Cmin) of Avelumab

  PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)

Study Arms (6)

Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg

EXPERIMENTAL

Participants received M9241 at a dose of 4 micrograms per kilogram (mcg/kg) a subcutaneous (SC) injection at time (up to -20 minutes) relative to the start of Avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks on Day 1 and 15 during each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met.

Drug: Avelumab; Drug: M9241; Drug: M9241 (MTD)

Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg

EXPERIMENTAL

Participants received M9241 at a dose of 8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met.

Drug: Avelumab; Drug: M9241

Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg

EXPERIMENTAL

Participants received M9241 at a dose of 12 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met.

Drug: Avelumab; Drug: M9241

Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg

EXPERIMENTAL

Participants received M9241 at a dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met.

Drug: Avelumab; Drug: M9241

Part A Cohort 5: M9241 16.8 mcg/kg + Avelumab 800 mg

EXPERIMENTAL

Participants received M9241 at a dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 800 milligrams (mg) IV infusion once weekly for the first 12 weeks, then 800 mg once every 2 weeks of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met.

Drug: Avelumab (Once weekly)

Part B Cohort 1: UC Cohort Stage 1 combination therapy

EXPERIMENTAL

Participants in the expansion cohorts received M9241 at dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks on Day 1 in combination with Avelumab 800 mg IV infusion once weekly for the first 12 weeks, then 800 mg once every 2 weeks of each cycle (Each cycle=28 days) determined as the RP2D in the escalation part of the study.

Drug: Avelumab (Once weekly); Drug: Avelumab (Expansion cohort)

Interventions

Avelumab DRUG

Participants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.

Also known as: MSB0010718C

Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg; Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg; Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg; Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg

M9241 DRUG

Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.

Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg; Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg; Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg; Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg

Avelumab (Once weekly) DRUG

Participants received avelumab once weekly in combination with M9241 every 4 weeks at M9241 maximum tolerated dose (MTD) for first 12 weeks followed by avelumab once every 2 weeks plus M9241 once every 4 weeks at M9241 MTD until a criterion for treatment discontinuation has been met.

Part A Cohort 5: M9241 16.8 mcg/kg + Avelumab 800 mg; Part B Cohort 1: UC Cohort Stage 1 combination therapy

M9241 (MTD) DRUG

Participants received M9241 at M9241 MTD once every 4 weeks until a criterion for treatment discontinuation has been met.

Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg

Avelumab (Expansion cohort) DRUG

Participants in the expansion cohorts received Induction Therapy (Avelumab once weekly + M9241 once every 4 weeks) through Cycle 3 (for 12 weeks) then starting at Cycle 4, Continuation Therapy (Avelumab once every 2 weeks + M9241 once every 4 weeks).

Part B Cohort 1: UC Cohort Stage 1 combination therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A:
• subjects must had signed written informed consent.
• male or female subjects age greater than equals to (\>=)18 years.
• subjects must had histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists, standard therapy had failed, subject was intolerant of established therapy known to provided clinical benefit for their condition, or standard therapy was not acceptable to subject.
• subjects who had been treated previously with a checkpoint inhibitor may enroll (except as outlined below for expansion cohorts).
• at least 1 unidimensional radiographically measurable lesion based on response evaluation criteria in solid tumors (recist) version 1. 1 (v1. 1), except for subjects with metastatic castration-resistant prostate cancer (crpc) or metastatic breast cancer who may been enrolled with objective evidence of disease without a measureable lesion. - eastern cooperative oncology group (ecog) performance status of 0 to 1 at screening
• estimated life expectancy of more than 12 weeks
• adequate hematological function as defined below:
• white blood cells (wbc) count \>= 3. 0 × 10\^9 per liter (/l)
• absolute neutrophil count \>= 1. 5 × 10\^9/l
• lymphocyte count \>= 0. 5 × 10\^9/l
• platelet count \>= 100 × 10\^9/l
• hemoglobin \>= 9 gram per deciliter (g/dl) (may had been transfused)
• adequate hepatic function as defined below:
• a total bilirubin level less than equals to (\<=) 1. 5 × upper limit of normal (uln) range

You may not qualify if:

• Concurrent treatment with a non-permitted drug/intervention (listed below)
• Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug within 4 weeks or 5 half-lives, whichever was shorter, prior to start of trial treatment, or not recovered from adverse event (AE) related to such therapies, with the following exceptions: Palliative radiotherapy delivered in a normal organ-sparing technique is permitted; Erythropoietin, darbepoetin-α and granulocyte colony-stimulating factor permitted; Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis permitted (i.e. luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy was permitted.
• Major surgery (as deemed by Investigator) for any reason, except diagnostic biopsy, within 4 weeks prior to start of trial treatment, or not fully recovered from surgery within 4 weeks prior to start of trial treatment.
• Participants receiving immunosuppressive agents (such as steroids) for any reason were tapered off these drugs before start of trial treatment, with following exceptions: Participants with adrenal insufficiency, continued corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily; Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) was permitted; Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon was acceptable as long as it was anticipated that the administration of steroids would be completed in 14 days, or that the dose after 14 days would be equivalent to \<= 10 mg prednisone daily.
• Any prior treatment with any form of interlukin-12 (IL-12)
• For the NSCLC, CRC, and UC expansion cohorts, prior therapy with any antibody / drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) antibody was prohibited.
• Intolerance to checkpoint inhibitor therapy, as defined by the occurrence of an AE requiring drug discontinuation. - Active or history of primary or metastatic central nervous system tumors
• Prior organ transplantation, including allogeneic stem-cell transplantation
• Previous malignant disease (other than the indication for this trial) within the last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to trial entry and subject was deemed to have been cured with no additional therapy required or anticipated to be required.
• Significant acute or chronic infections requiring systemic therapy including, among others:
• History of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome • Hepatitis B or C infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV deoxy ribonucleic acid (DNA) or HBV core antibody positive alone with reflex to positive HBV DNA or positive hepatitis C virus \[HCV\] antibody with reflex to positive HCV ribonucleic acid \[RNA\]). Participants with history of infection must had polymerase chain reaction documentation that infection was cleared.
• History of allergic reaction to methotrexate (trace methotrexate may be present in M9241 as a part of manufacturing process) or history of severe hypersensitivity reaction to any other ingredient of study drug(s) and / or their excipients. Since M9241 contains sucrose as an excipient, participants suffering from hereditary fructose intolerance also excluded - Persisting toxicity related to prior therapy of Grade \> 1 NCI-CTCAE v4.03 with the following exceptions:
• Neuropathy Grade \<= 2 was acceptable.
• All grades of alopecia acceptable.
• Endocrine dysfunction on replacement therapy was acceptable.

Sponsors & Collaborators

• EMD Serono Research & Development Institute, Inc.: lead
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (33)

California Cancer Associates for Research & Excellence, Inc.

San Diego, California, 92111, United States

Location

Sharp Memorial Hospital

San Diego, California, 92123, United States

Location

St Joseph Heritage Healthcare

Santa Rosa, California, 95403, United States

Location

Yale University Institutional Review Board

New Haven, Connecticut, 06520, United States

Location

Holy Cross Hospital Inc.

Fort Lauderdale, Florida, 33308, United States

Location

Hematology - Oncology Associates of the Treasure Coast

Port Saint Lucie, Florida, 34952, United States

Location

Metairie Oncologists, LLC

Metairie, Louisiana, 70006, United States

Location

National Cancer Institute

Bethesda, Maryland, 20892, United States

Location

Virginia Piper Cancer Institute

Minneapolis, Minnesota, 55407, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

UC Health, LLC.

Cincinnati, Ohio, 45229, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Cedar Sinai Medical Center

Ashland, Oregon, 97520, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Mary Crowley Cancer Research Centers

Dallas, Texas, 75251, United States

Location

University of Vermont Medical Center

Burlington, Vermont, 05405, United States

Location

Northwest Medical Specialties, PLLC

Tacoma, Washington, 98405, United States

Location

Centre Hospitalier de l'Ardenne - Pharmacie

Libramont, Belgium

Location

GZA Ziekenhuizen - Campus Sint-Augustinus

Wilrijk, Belgium

Location

CHU Bordeaux - Hôpital Saint André

Bordeaux, France

Location

Centre Georges François Leclerc

Dijon, France

Location

Centre Oscar Lambret

Lille, France

Location

Hôpital de la Timone# - CPCEM CIC - Bat F 1er étage

Marseille, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Orszagos Onkologiai Intezet

Budapest, Hungary

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

Location

IOV - Istituto Oncologico Veneto IRCCS

Padua, Italy

Location

A.O.U. Senese Policlinico Santa Maria alle Scotte

Siena, Italy

Location

Amsterdam UMC, Locatie VUMC

Amsterdam, Netherlands

Location

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, Netherlands

Location

Maastricht University Medical Center

Maastricht, Netherlands

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Related Publications (1)

• Strauss J, Deville JL, Sznol M, Ravaud A, Maruzzo M, Pachynski RK, Gourdin TS, Maio M, Dirix L, Schlom J, Donahue RN, Tsai YT, Wang X, Vugmeyster Y, Beier F, Seebeck J, Schroeder A, Chennoufi S, Gulley JL. First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma. J Immunother Cancer. 2023 May;11(5):e005813. doi: 10.1136/jitc-2022-005813.

  PMID: 37236636 RESULT

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources

MeSH Terms

Interventions

avelumab; Maximum Tolerated Dose

Intervention Hierarchy (Ancestors)

Toxicity Tests; Investigative Techniques; Toxicological Phenomena; Pharmacological and Toxicological Phenomena; Physiological Phenomena

Limitations and Caveats

The study was terminated due to pre-specified futility criteria met.

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@merckgroup.com

6151 72 5200

Study Officials

• Medical Responsible

  EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2016
• First Posted: December 16, 2016
• Study Start: January 31, 2017
• Primary Completion: October 8, 2020
• Study Completion: October 8, 2020
• Last Updated: September 20, 2024
• Results First Posted: September 20, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1); NL (3); FR (6); BE (2); IT (3); US (17); HU (1)