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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Avelumab
* Drug: M9241
* Drug: Avelumab (Once weekly)
* Drug: M9241 (MTD)
* Drug: Avelumab (Expansion cohort)


Participation Criteria
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Eligibility Criteria
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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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Avelumab and M9241<br> | Drug: Avelumab<br>* Subjects will receive avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.<br>* Other names: MSB0010718C;Drug: M9241<br>* Subjects will receive Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.<br>|
| Experimental: Avelumab (once weekly) + M9241 (MTD)<br> | Drug: Avelumab (Once weekly)<br>* Subjects will receive 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.<br>Drug: M9241 (MTD)<br>* Subjects will receive M9241 at M9241 MTD once every 4 weeks until a criterion for treatment discontinuation has been met.<br>|
| Experimental: Avelumab (once weekly) + M9241 (RP2D) (Expansion cohort)<br> | Drug: Avelumab (Expansion cohort)<br>* Subjects in the expansion cohorts will receive 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and B: Occurrence and Severity of Treatment Emergent Adverse Events (TEAEs) and related TEAEs |  | Up to 222 Weeks | 
| Part A: Number of Subjects With Dose Limiting Toxicities (DLTs) |  | Up to 3 weeks | 
| Part A: Duration of TEAEs and Related TEAEs |  | Up to 52 weeks | 
| Part B: Best Overall Response (BOR) by Investigator Assessment |  | Up to 222 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Area Under the Concentration Time Curve from time of dosing to infinity (AUC0-inf) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Terminal Elimination Rate Constant (λz) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Maximum Serum Concentration (Cmax) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Minimum Serum Concentration (Cmin) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Time to Reach Maximum Concentration Cmax (Tmax) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Apparent Terminal Half-life (t1/2) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: AUC From the Time of Dosing to the Dosing Interval Tau (AUCtau) of Avelumab |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion | 
| Part A: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Area Under the Concentration Time Curve from time of dosing to infinity (AUC0-inf) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Terminal Elimination Rate Constant (λz) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Maximum Serum Concentration (Cmax) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Minimum Serum Concentration (Cmin) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Time to Reach Maximum Concentration Cmax (Tmax) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Apparent Terminal Half-life (t1/2) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: AUC From the Time of Dosing to the Dosing Interval Tau (AUCtau) of M9241 |  | Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion | 
| Part A: Immunogenicity of Avelumab and M9241 Measured by ADA Assays |  | At screening and Pre-dose at Day 15 | 
| Part A: Confirmed Best Overall Response (BOR) According to RECIST v1.1 Criteria |  | Up to 52 weeks | 
| Part A: Immune-related BOR Using Immune-related Response Criteria, Derived From RECIST v1.1 |  | Up to 52 weeks | 
| Part B: Progression Free Survival (PFS) According to RECIST v1.1 Criteria Assessed by Investigator |  | Baseline until progressive disease or death, assessed up to 222 weeks | 
| Part B: Overall Survival (OS) |  | Baseline until death, assessed up to 222 weeks | 
| Part B: Duration of Response According to RECIST v1.1 Criteria Assessed by Investigator |  | Baseline until 222 weeks | 
| Part B: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Area Under the Concentration Time Curve From Time of Dosing to Infinity (AUC0-inf) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Terminal Elimination Rate Constant (λz) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Maximum Serum Concentration (Cmax) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Minimum Serum Concentration (Cmin) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Time to Reach Maximum Concentration Cmax (Tmax) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Apparent Terminal Half-life (t1/2) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: AUC From the Time of Dosing to the Dosing Interval Tau (AUCtau) of Avelumab and M9241 |  | Pre-dose, 1 h post-infusion on Day 1 Cycle 1, Day 15 Cycle 1, Day 1 Cycle 2, 3, 4 and Day 3 Cycle 1, 2, 3, 4 (each cycle = 28 days) | 
| Part B: Immunogenicity of Avelumab and M9241 Measured by ADA Assays. |  | Pre-dose at Day 1 and Day 15 of Cycle 1, Pre-dose at Day 1 of Cycle 2 ,3 and 4 (each cycle = 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avelumab, M9241, NHS-IL12, Advanced Solid Tumors