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

NCT ID: NCT02994953

Last Updated: 2024-09-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-31
• Study Completion Date: 2020-10-08

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

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.

Group Type: EXPERIMENTAL

Avelumab

Intervention Type: DRUG

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

M9241

Intervention Type: DRUG

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

M9241 (MTD)

Intervention Type: DRUG

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

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

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.

Group Type: EXPERIMENTAL

Avelumab

Intervention Type: DRUG

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

M9241

Intervention Type: DRUG

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

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

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.

Group Type: EXPERIMENTAL

Avelumab

Intervention Type: DRUG

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

M9241

Intervention Type: DRUG

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

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

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.

Group Type: EXPERIMENTAL

Avelumab

Intervention Type: DRUG

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

M9241

Intervention Type: DRUG

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

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

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.

Group Type: EXPERIMENTAL

Avelumab (Once weekly)

Intervention Type: 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 B Cohort 1: UC Cohort Stage 1 combination therapy

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.

Group Type: EXPERIMENTAL

Avelumab (Once weekly)

Intervention Type: 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.

Avelumab (Expansion cohort)

Intervention Type: 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).

Interventions

Avelumab

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

Intervention Type: DRUG

M9241

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

Intervention Type: DRUG

Avelumab (Once weekly)

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.

Intervention Type: DRUG

M9241 (MTD)

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

Intervention Type: DRUG

Avelumab (Expansion cohort)

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).

Intervention Type: DRUG

Other Intervention Names

MSB0010718C

Eligibility Criteria

Inclusion Criteria

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
• aspartate aminotransferase (ast) levels <= 2. 5 × uln (≤ 3 × uln for expansion cohorts)
• alanine aminotransferase (alt) levels <= 2. 5 × uln (≤ 3 × uln for expansion cohorts)
• subjects with documented gilbert disease were allowed if total bilirubin > 1. 5 but less than 3 × uln
• adequate renal function as defined by an estimated creatinine clearance >= 50 milliliter per minute (ml/min) according to cockcroft-gault formula
• negative blood pregnancy test at screening for women of childbearing potential. For purposes of this trial, women of childbearing potential were defined as all female subjects after puberty unless they were postmenopausal for at least 1 year, surgically sterile or sexually inactive.
• highly effective contraception (ie, methods with a failure rate of less than 1% per year) must been used before started of treatment, for duration of trial treatment, and for at least 50 days after stopping studied treatment for both men and women if risk of conception exists. The effects of avelumab and m9241 on developing human fetus were unknown; thus, women of childbearing potential and men agreed to use highly effective contraception.

Part B:

• Availability of a fresh tumor biopsy was mandatory for eligibility in the RCC cohort. The biopsy or surgical specimen should be collected within 28 days prior to the first IMP administration. If a subject had 2 separate biopsy attempts in which usable tissue was not obtained, enrollment would have been possible after discussion with the Medical Monitor. For other expansion cohorts, availability of either tumor archival material (< 6 months old) or fresh biopsies (obtained within 28 days) was acceptable with one of these being mandatory. For formalin-fixed paraffin-embedded samples, either block or sections (> 15) provided. Tumor biopsies and tumor archival material should have been suitable for biomarker assessment - Locally advanced or metastatic UC that had progressed during or after at least one previous platinum-based chemotherapy and not previously treated with anti-PD-1/PD-L1 agents: Histologically or cytologically confirmed locally advanced or metastatic transitional cell carcinoma of urothelium(including renal pelvis, ureters, urinary bladder, and urethra). Participants must had progressed during or after treatment with at least 1 platinum-containing regimen for inoperable locally advanced or metastatic UC or disease recurrence. Participants who had received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing regimen were considered as second line. Participants with mixed histologies were required to have a dominant transitional cell pattern.
• Non-small cell lung cancer (NSCLC), first-line metastatic: Stage IV (per seventh International Association for the Study of Lung Cancer classification) histologically confirmed NSCLC. Participants must not had received treatment for their metastatic disease. Participants could have received adjuvant chemotherapy or loco-regional treatment that included chemotherapy for locally advanced disease, as long as disease recurrence occurred at least 6 months after the completion of the last administration of chemotherapy. Only epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type were allowed (ie, EGFR mutation and ALK translocation / re arrangement excluded). Non squamous cell histologies and never / former light smoker (< 15 pack years) squamous cell carcinoma Participants (per local standard of care) required testing if status was unknown. Participants must had low tumor PD-L1 expression defined as < 50% tumor proportion score determined using PD-L1 IHC 22C3 pharmDx test or an equivalent Food and Drug Administration (FDA)- approved PD-L1 test. Availability of either tumor archival material or fresh biopsies within 28 days was acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material had been suitable for biomarker assessment. This cohort would not be opened for enrollment in Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom.
• Colorectal cancer (CRC): Histologically or cytologically confirmed recurrent or refractory metastatic CRC (according to American Joint Committee on Cancer / International Union Against Cancer Tumor Node Metastasis [TNM] Staging System seventh edition) after failure of prior therapy containing oxaliplatin / fluoropyrimidine and / or irinotecan / fluoropyrimidine and, if eligible, cetuximab (Erbitux®) and bevacizumab (Avastin®). Only Participants with microsatellite instability (MSI)-low or microsatellite stable (MSS) metastatic CRC are eligible. Participants without existing MSI test results had MSI status performed locally by a Clinical Laboratory Improvement Amendments (CLIA)-certified IHC or polymerase chain reaction (PCR)-based test (PCR based MSI test is preferred). Participants had to be willing to undergo an on-treatment biopsy procedure. Availability of either tumor archival material or fresh biopsies within 28 days was acceptable with one of these being mandatory. For FFPE samples, either a block or sections (> 15) could be provided. Tumor biopsies and tumor archival material had to be suitable for biomarker assessment. For Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom, participants in the second-line setting had exhausted or were considered ineligible or intolerant (in the opinion of the Investigator) of available second-line chemotherapy options.
• Renal cell carcinoma (RCC), primary immune checkpoint inhibitor failure: Histologically or cytologically documented metastatic RCC with a component of clear cell subtype. Participants must have had progressive disease (PD) within 6 months or best overall response of stable disease (SD) for ≥ 6 months following start of 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) for advanced or metastatic disease (either as monotherapy or combination therapy, in any line). Fresh tumor biopsy was required for enrollment. If a subject had 2 separate biopsy attempts in which usable tissue was not obtained, enrollment could be possible after discussion with the Medical Monitor. Participants had to be willing to undergo an on-treatment biopsy procedure. In France, in addition to having received checkpoint inhibitor therapy, participants should have already received recommended local-standard therapy per discretion of the Investigator.

Exclusion Criteria

• 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.
• Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment wer eligible if they wer stable on other medical treatment and do not fulfill exclusion criterion including Uncontrolled intercurrent illness - Known severe hypersensitivity reactions to monoclonal antibodies (Grade>= 3 National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma)
• 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.
• Pregnancy or lactation
• Known alcohol or drug abuse as deemed by the Investigator
• Uncontrolled intercurrent illness including, but not limited to:

• Hypertension uncontrolled by standard therapies (not stabilized to 150/90 millimeter of mercury (mm Hg) or lower)
• Uncontrolled active infection
• Uncontrolled diabetes (eg, glycosylated hemoglobin [HgbA1c] >= 8%)
• Clinically significant (or active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), or serious cardiac arrhythmia requiring medication
• All other significant diseases (eg, inflammatory bowel disease, current severe acute or chronic colitis) or chronic medical conditions (including laboratory abnormalities) that in opinion of Investigator might impair subject's tolerance of trial treatment or interpretation of trial results.
• Any psychiatric condition that would prohibit understanding or endering of informed consent or that would limit compliance with trial requirements.
• Legal incapacity or limited legal capacity.
• Administration of a live vaccine within 30 days prior to trial entry.
• Any subject with possible area of ongoing necrosis (non-disease related), such as active ulcer, non-healing wound, or intercurrent bone fracture that may be at risk of delayed healing due to protocol therapy.
• Oxygen saturation < 90% at rest, known pulmonary fibrosis, or active interstitial lung disease.
• History of congenital or active immunodeficiency, with exception of acquired treatment-related hypogammaglobulinemia requiring periodic IV immunoglobulin infusion.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck KGaA, Darmstadt, Germany

INDUSTRY

Sponsor Role: collaborator

EMD Serono Research & Development Institute, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Responsible

Role: STUDY_DIRECTOR

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

Locations

California Cancer Associates for Research & Excellence, Inc.

San Diego, California, United States

Sharp Memorial Hospital

San Diego, California, United States

St Joseph Heritage Healthcare

Santa Rosa, California, United States

Yale University Institutional Review Board

New Haven, Connecticut, United States

Holy Cross Hospital Inc.

Fort Lauderdale, Florida, United States

Hematology - Oncology Associates of the Treasure Coast

Port Saint Lucie, Florida, United States

Metairie Oncologists, LLC

Metairie, Louisiana, United States

National Cancer Institute

Bethesda, Maryland, United States

Virginia Piper Cancer Institute

Minneapolis, Minnesota, United States

Washington University

St Louis, Missouri, United States

UC Health, LLC.

Cincinnati, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Cedar Sinai Medical Center

Ashland, Oregon, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Mary Crowley Cancer Research Centers

Dallas, Texas, United States

University of Vermont Medical Center

Burlington, Vermont, United States

Northwest Medical Specialties, PLLC

Tacoma, Washington, United States

Centre Hospitalier de l'Ardenne - Pharmacie

Libramont, , Belgium

GZA Ziekenhuizen - Campus Sint-Augustinus

Wilrijk, , Belgium

CHU Bordeaux - Hôpital Saint André

Bordeaux, , France

Centre Georges François Leclerc

Dijon, , France

Centre Oscar Lambret

Lille, , France

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

Marseille, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

Centre Paul Strauss

Strasbourg, , France

Orszagos Onkologiai Intezet

Budapest, , Hungary

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, , Italy

IOV - Istituto Oncologico Veneto IRCCS

Padua, , Italy

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

Siena, , Italy

Amsterdam UMC, Locatie VUMC

Amsterdam, , Netherlands

Antoni van Leeuwenhoek Ziekenhuis

Amsterdam, , Netherlands

Maastricht University Medical Center

Maastricht, , Netherlands

Hospital Universitario Virgen del Rocio

Seville, , Spain

Countries

United States; Belgium; France; Hungary; Italy; Netherlands; Spain

References

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.

Reference Type: RESULT

PMID: 37236636 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.emdgroup.com/en/trial-details/?id=MS201781_0031

Trial Awareness and Transparency website

https://medical.emdserono.com/en_US/home.html

US Medical Information website, Medical Resources

Other Identifiers

2017-002212-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MS201781_0031

Identifier Type: -

Identifier Source: org_study_id