A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12) (JAVELIN IL-12) (COMBO)
Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
Details and patient eligibility
About
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).
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Part A:
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subjects must had signed written informed consent.
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male or female subjects age greater than equals to (>=)18 years.
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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.
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subjects who had been treated previously with a checkpoint inhibitor may enroll (except as outlined below for expansion cohorts).
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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
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estimated life expectancy of more than 12 weeks
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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)
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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
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adequate renal function as defined by an estimated creatinine clearance >= 50 milliliter per minute (ml/min) according to cockcroft-gault formula
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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.
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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
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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.
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Any prior treatment with any form of interlukin-12 (IL-12)
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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.
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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
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Prior organ transplantation, including allogeneic stem-cell transplantation
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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.
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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.
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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)
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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.
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Pregnancy or lactation
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Known alcohol or drug abuse as deemed by the Investigator
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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%)
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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
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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.
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Any psychiatric condition that would prohibit understanding or endering of informed consent or that would limit compliance with trial requirements.
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Legal incapacity or limited legal capacity.
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Administration of a live vaccine within 30 days prior to trial entry.
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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.
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Oxygen saturation < 90% at rest, known pulmonary fibrosis, or active interstitial lung disease.
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History of congenital or active immunodeficiency, with exception of acquired treatment-related hypogammaglobulinemia requiring periodic IV immunoglobulin infusion.
Trial design
Primary purpose
Allocation
Interventional model
Masking
52 participants in 6 patient groups
Trial contacts and locations
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Data sourced from clinicaltrials.gov
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