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

A Phase Ib Open-Label, Dose-Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination With M9241(NHS-IL12) in Subjects With Locally Advanced, Unresectable, or Metastatic Solid Tumors

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).

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: Avelumab; Drug: M9241; Drug: M9241 (MTD); Drug: Avelumab (Once weekly); Drug: Avelumab (Expansion cohort)

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Libramont, Belgium
    • Centre Hospitalier de l'Ardenne - Pharmacie
  • Wilrijk, Belgium
    • GZA Ziekenhuizen - campus Sint-Augustinus
• France
  • Bordeaux cedex, France
    • CHU Bordeaux - Hôpital Saint André
  • Dijon cedex, France
    • Centre Georges Francois Leclerc
  • Lille cedex, France
    • Centre Oscar Lambret
  • Marseille cedex 5, France
    • Hôpital de la Timone# - CPCEM CIC - Bat F 1er étage
  • Pierre Benite cedex, France
    • Centre Hospitalier Lyon Sud
  • Strasbourg Cedex, France
    • Centre Paul Strauss
• Hungary
  • Budapest, Hungary
    • Orszagos Onkologiai Intezet
• Italy
  • Milano, Italy
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Padova, Italy
    • Iov - Istituto Oncologico Veneto Irccs
  • Siena, Italy
    • A.O.U. Senese Policlinico Santa Maria alle Scotte
• Netherlands
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek Ziekenhuis
  • Amsterdam, Netherlands
    • Amsterdam UMC, locatie VUmc
  • Maastricht, Netherlands
    • Maastricht University Medical Center
• Spain
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocio
• United States
  • California
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital
    • San Diego, California, United States, 92111
      • California Cancer Associates for Research & Excellence, Inc.
    • Santa Rosa, California, United States, 95403
      • St Joseph Heritage Healthcare
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University Institutional Review Board
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital Inc.
    • Port Saint Lucie, Florida, United States, 34952
      • Hematology - Oncology Associates of the Treasure Coast
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Metairie Oncologists, LLC
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • UC Health, LLC.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Ashland, Oregon, United States, 97520
      • Cedar Sinai Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75251
      • Mary Crowley Cancer Research Centers
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont Medical Center
  • Washington
    • Tacoma, Washington, United States, 98405
      • NorthWest Medical Specialties, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Avelumab; Participants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.; Other Names: MSB0010718C; Drug: M9241; Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.; Drug: M9241 (MTD); Participants received M9241 at M9241 MTD once every 4 weeks until a criterion for treatment discontinuation has been met.
Experimental: 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.	Drug: Avelumab; Participants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.; Other Names: MSB0010718C; Drug: M9241; Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.
Experimental: 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.	Drug: Avelumab; Participants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.; Other Names: MSB0010718C; Drug: M9241; Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.
Experimental: 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.	Drug: Avelumab; Participants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.; Other Names: MSB0010718C; Drug: M9241; Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.
Experimental: 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.	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.
Experimental: 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.	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.; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of Avelumab	Area under the serum concentration versus time curve from time zero to the last sampling time t at which concentration is at or above the lower limit of quantification (LLLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.	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	The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.	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	Lambda(z) was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.	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	Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.	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	Cmin is minimum observed serum concentration obtained directly from the concentration versus time curve.	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: Time to Reach Maximum Observed Concentration (Tmax) of Avelumab	Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.	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: Apparent Terminal Half-life (t1/2) of Avelumab	Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination.	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: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of Avelumab	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	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: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of M9241	Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). (AUC0-t) was calculated according to the mixed log-linear trapezoidal rule.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M9241	The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Terminal Elimination Rate Constant (Lambdaz) of M9241	Lambda(z) was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Maximum Observed Serum Concentration (Cmax) of M9241	Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Minimum Observed Serum Concentration (Cmin) of M9241	Cmin is minimum observed serum concentration obtained directly from the concentration versus time curve.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Time to Reach Maximum Observed Concentration (Tmax) of M9241	Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Apparent Terminal Half-life (t1/2) of M9241	Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination.	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M9241	AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) for Avelumab and M9241	ADA category of each participant was classified as pre-existing immunoreactivity (positive ADA response at baseline (prior to treatment), treatment-boosted (positive response at baseline with at least one post baseline titer at >=8-fold baseline titer), or treatment-emergent (TE [any positive post baseline assay response when baseline results were negative or missing or not reported]). TE ADA responses were further classified as persistent (treatment-emergent positive ADA response detected in at least 2 consecutive post baseline samples separated by at least a 16-week post baseline period [based on nominal sampling time], with no ADA-negative samples in-between or positive response at last ADA sampling time point) and transient (not persistent/indeterminate, regardless of any missing samples).	First dose of study drug up to 1311 days
Part A: Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1	BOR is defined as best response of any of confirmed complete response, confirmed partial response, stable disease and progressive disease recorded from date of randomization until disease progression or recurrence. 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. Non-CR/non-PD (for participants with non-measurable disease at baseline) = at least one Non-CR/non-PD assessment (or better) >= 6 weeks after first study treatment administration and before progression and Not Evaluable: all other cases. BOR assessments were assessed by investigators.	First dose of study drug up to 1311 days
Pat A: Number of Participants With Immune-related Best Overall Response (BOR) Using Immune-related Response Criteria Derived From Response Evaluation Criteria in Solid Tumors Version 1.1	BOR: best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). irCR: Complete disappearance of all tumor lesions (both index and non-index lesions with no new measurable/unmeasurable lesions). irPR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions). irSD: SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD: SLD of target and new measurable lesions increases greater than or equal to [>=] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category (irCR, irPR, irSD, irPD) was reported.	First dose of study drug up to 1311 days
Part B: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by Investigator	PFS was defined as the time from first treatment day until date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier estimates.	Time from first dose administration until progressive disease or death, assessed up to 443 days
Part B: Overall Survival (OS) Time	The OS time was defined as the time from treatment day 1 to the date of death due to any cause. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier estimates.	Time from first dose of study treatment up to 443 days
Part B: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by Investigator	DOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of objective progression of disease (PD) or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as 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. If a participant has not an event (PD or death), DOR was censored at the date of last adequate tumor assessment.	Time from first dose of study treatment up to 443 days
Part B: Maximum Observed Serum Concentration (Cmax) of M9241	Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.	Pre-dose, 1 hour post-dose on Day 1 and Day 29 of Cycle 1 and 2 (Each cycle: 28 days)
Part B: Serum Trough Concentration Levels (Ctrough) of M9241	Ctrough was defined as the trough or minimum serum concentration.	Pre-dose, 1 hour post-dose on Day 1 of cycle 2; Day 1, 27 of cycle 3; Day 1 of cycle 5 (Each cycle: 28 days)
Part B: Concentration at the End of Infusion (Ceoi) of Avelumab	Ceoi is the observed serum drug concentration at the end of Intravenous (IV) infusion.	Pre-dose, 1 hour post-dose on Day 1 and 15 of Cycle 1 and 2 (Each cycle: 28 days)
Part B: Serum Trough Concentration Levels (Ctrough) of Avelumab	Ctrough was defined as the trough or minimum serum concentration.	Pre-dose, 1 hour post-dose on Day 15, 29 and 43
Part B: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) of Avelumab and M9241	ADA category of each participant was classified as pre-existing immunoreactivity (positive ADA response at baseline (prior to treatment), treatment-boosted (positive response at baseline with at least one post baseline titer at >=8-fold baseline titer), or treatment-emergent (TE [any positive post baseline assay response when baseline results were negative or missing or not reported]). TE ADA responses were further classified as persistent (treatment-emergent positive ADA response detected in at least 2 consecutive post baseline samples separated by at least a 16-week post baseline period [based on nominal sampling time], with no ADA-negative samples in-between or positive response at last ADA sampling time point) and transient (not persistent/indeterminate, regardless of any missing samples).	Time from first dose of study treatment up to 443 days

Collaborators and Investigators

• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• 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.

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2017
• Primary Completion (Actual): October 8, 2020
• Study Completion (Actual): October 8, 2020

Study Registration Dates

• First Submitted: December 14, 2016
• First Submitted That Met QC Criteria: December 14, 2016
• First Posted (Estimated): December 16, 2016

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Avelumab; Advanced Solid Tumors; NHS-IL12; M9241
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Avelumab; Antibodies, Monoclonal
• Other Study ID Numbers: MS201781_0031; 2017-002212-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No