MedPath

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

Phase 1
Terminated
Conditions
Advanced Solid Tumors
Interventions
Drug: Avelumab (Once weekly)
Drug: Avelumab
Drug: M9241
Drug: Avelumab (Expansion cohort)
Drug: M9241 (MTD)
Registration Number
NCT02994953
Lead Sponsor
EMD Serono Research & Development Institute, Inc.
Brief Summary

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

Detailed Description

Not available

Recruitment & Eligibility

Status
TERMINATED
Sex
All
Target Recruitment
52
Inclusion Criteria

Part A:

  • Subjects must have signed written informed consent.

  • Male or female subjects age greater than equals to (>=)18 years.

  • Subjects must have histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists, standard therapy has failed, subject is intolerant of established therapy known to provide clinical benefit for their condition, or standard therapy is not acceptable to subject.

  • Subjects who have 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 be 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 have been transfused)

  • Adequate hepatic function as defined below:

    • A total bilirubin level lass 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 are 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 are defined as all female subjects after puberty unless they are 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 be used before start of treatment, for duration of trial treatment, and for at least 50 days after stopping study treatment for both men and women if risk of conception exists. The effects of avelumab and M9241 on developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception.

Part B:

  • Availability of a fresh tumor biopsy is 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 has 2 separate biopsy attempts in which usable tissue is not obtained, enrollment may be 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) is acceptable with one of these being mandatory. For formalin-fixed paraffin-embedded samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment
  • Locally advanced or metastatic UC that has 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). Subjects must have progressed during or after treatment with at least 1 platinum-containing regimen for inoperable locally advanced or metastatic UC or disease recurrence. Subjects who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing regimen will be considered as second line. Subjects with mixed histologies are 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. Subjects must not have received treatment for their metastatic disease. Subjects 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 are 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 subjects (per local standard of care) require testing if status is unknown. Subjects must have 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 is acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment. This cohort will 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 subjects with microsatellite instability (MSI)-low or microsatellite stable (MSS) metastatic CRC are eligible. Subjects without existing MSI test results will have 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). Subjects must be willing to undergo an on-treatment biopsy procedure. Availability of either tumor archival material or fresh biopsies within 28 days is acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material must be suitable for biomarker assessment. For Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom, subjects in the second-line setting should have exhausted or be 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. Subjects 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 is required for enrollment. If a subject has 2 separate biopsy attempts in which usable tissue is not obtained, enrollment may be possible after discussion with Medical Monitor. Subjects must be willing to undergo an on-treatment biopsy procedure. In France, in addition to having received checkpoint inhibitor therapy, subjects should have already received recommended local-standard therapy per discretion of the Investigator.
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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 is 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 is 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.
    • Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before start of trial treatment, with following exceptions: Subjects with adrenal insufficiency, may continue 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) is permitted; Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the dose after 14 days will 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 is 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]). Subjects with history of infection must have polymerase chain reaction documentation that infection is cleared.

  • Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible if they are 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, subjects 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 is acceptable.
    • All grades of alopecia acceptable.
    • Endocrine dysfunction on replacement therapy is 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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Part A Cohort 5: M9241 16.8 mcg/kg + Avelumab 800 mgAvelumab (Once weekly)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.
Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kgAvelumabParticipants 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.
Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kgM9241Participants 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.
Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kgM9241 (MTD)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.
Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kgM9241Participants 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.
Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kgAvelumabParticipants 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.
Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kgM9241Participants 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.
Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kgAvelumabParticipants 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.
Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kgM9241Participants 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.
Part B Cohort 1: UC Cohort Stage 1 combination therapyAvelumab (Once weekly)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.
Part B Cohort 1: UC Cohort Stage 1 combination therapyAvelumab (Expansion cohort)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.
Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kgAvelumabParticipants 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.
Primary Outcome Measures
NameTimeMethod
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) v4.03From first dose of study treatment up to 1311 days

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: 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) v4.03Part B: From first dose of study treatment up to 443 days

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 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)From first dose of study treatment up to 1311 days

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.

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)First dose of study drug up to 443 days

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.

Part A: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)Time from first treatment to final assessment up to 3 weeks

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.

Part B: Number of Participants With Confirmed Best Overall Response (BOR) Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1First dose of study drug up to 443 days

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.

Secondary Outcome Measures
NameTimeMethod
Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of AvelumabPredose (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)

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.

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

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Part A: Terminal Elimination Rate Constant (Lambdaz) of AvelumabPrD, 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)

Lambda(z) was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.

Part A: Maximum Observed Serum Concentration (Cmax) of AvelumabPrD, 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)

Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.

Part A: Minimum Observed Serum Concentration (Cmin) of AvelumabPrD, 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)

Cmin is minimum observed serum concentration obtained directly from the concentration versus time curve.

Part A: Time to Reach Maximum Observed Concentration (Tmax) of AvelumabPrD, 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)

Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.

Part A: Apparent Terminal Half-life (t1/2) of AvelumabPrD, 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)

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.

Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of AvelumabPrD, 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)

AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of M9241PrD, 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)

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.

Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M9241PrD, 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)

The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Part A: Terminal Elimination Rate Constant (Lambdaz) of M9241PrD, 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)

Lambda(z) was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.

Part A: Maximum Observed Serum Concentration (Cmax) of M9241PrD, 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)

Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.

Part A: Minimum Observed Serum Concentration (Cmin) of M9241PrD, 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)

Cmin is minimum observed serum concentration obtained directly from the concentration versus time curve.

Part A: Time to Reach Maximum Observed Concentration (Tmax) of M9241PrD, 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)

Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.

Part A: Apparent Terminal Half-life (t1/2) of M9241PrD, 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)

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.

Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M9241PrD, 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)

AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Part A: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) for Avelumab and M9241First dose of study drug up to 1311 days

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).

Part A: Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1First dose of study drug up to 1311 days

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.

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 1.1First dose of study drug up to 1311 days

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.

Part B: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by InvestigatorTime from first dose administration until progressive disease or death, assessed up to 443 days

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.

Part B: Overall Survival (OS) TimeTime from first dose of study treatment up to 443 days

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.

Part B: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by InvestigatorTime from first dose of study treatment up to 443 days

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.

Part B: Maximum Observed Serum Concentration (Cmax) of M9241Pre-dose, 1 hour post-dose on Day 1 and Day 29 of Cycle 1 and 2 (Each cycle: 28 days)

Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.

Part B: Serum Trough Concentration Levels (Ctrough) of M9241Pre-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)

Ctrough was defined as the trough or minimum serum concentration.

Part B: Concentration at the End of Infusion (Ceoi) of AvelumabPre-dose, 1 hour post-dose on Day 1 and 15 of Cycle 1 and 2 (Each cycle: 28 days)

Ceoi is the observed serum drug concentration at the end of Intravenous (IV) infusion.

Part B: Serum Trough Concentration Levels (Ctrough) of AvelumabPre-dose, 1 hour post-dose on Day 15, 29 and 43

Ctrough was defined as the trough or minimum serum concentration.

Part B: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) of Avelumab and M9241Time from first dose of study treatment up to 443 days

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).

Trial Locations

Locations (33)

St Joseph Heritage Healthcare

🇺🇸

Santa Rosa, California, United States

Metairie Oncologists, LLC

🇺🇸

Metairie, Louisiana, United States

IOV - Istituto Oncologico Veneto IRCCS

🇮🇹

Padova, Italy

CHU Bordeaux - Hôpital Saint André

🇫🇷

Bordeaux cedex, France

Centre Georges François Leclerc

🇫🇷

Dijon cedex, France

Centre Oscar Lambret

🇫🇷

Lille cedex, France

Hematology - Oncology Associates of the Treasure Coast

🇺🇸

Port Saint Lucie, Florida, United States

Cedar Sinai Medical Center

🇺🇸

Ashland, Oregon, United States

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

🇫🇷

Marseille cedex 5, France

Fondazione IRCCS Istituto Nazionale dei Tumori

🇮🇹

Milano, Italy

Centre Hospitalier de l'Ardenne - Pharmacie

🇧🇪

Libramont, Belgium

Washington University

🇺🇸

Saint Louis, Missouri, United States

GZA Ziekenhuizen - Campus Sint-Augustinus

🇧🇪

Wilrijk, Belgium

Orszagos Onkologiai Intezet

🇭🇺

Budapest, Hungary

Hospital Universitario Virgen del Rocio

🇪🇸

Sevilla, Spain

Holy Cross Hospital Inc.

🇺🇸

Fort Lauderdale, Florida, United States

University of Vermont Medical Center

🇺🇸

Burlington, Vermont, United States

California Cancer Associates for Research & Excellence, Inc.

🇺🇸

San Diego, California, United States

Sharp Memorial Hospital

🇺🇸

San Diego, California, United States

UC Health, LLC.

🇺🇸

Cincinnati, Ohio, United States

Centre Hospitalier Lyon Sud

🇫🇷

Pierre Benite cedex, France

Mary Crowley Cancer Research Centers

🇺🇸

Dallas, Texas, United States

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

Northwest Medical Specialties, PLLC

🇺🇸

Tacoma, Washington, United States

Centre Paul Strauss

🇫🇷

Strasbourg Cedex, France

National Cancer Institute

🇺🇸

Bethesda, Maryland, United States

Virginia Piper Cancer Institute

🇺🇸

Minneapolis, Minnesota, United States

Yale University Institutional Review Board

🇺🇸

New Haven, Connecticut, United States

University of Oklahoma Health Sciences Center

🇺🇸

Oklahoma City, Oklahoma, United States

Medical University of South Carolina

🇺🇸

Charleston, South Carolina, United States

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