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

NCT02994953

Description:

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 NHS-IL12 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 NHS-IL12, 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 NHS-IL12 with avelumab intravenous (IV).

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Renal Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12)
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: MS201781_0031
  • NCT ID: NCT02994953

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
AvelumabMSB0010718CAvelumab and NHS-IL12
NHS-IL12Avelumab and NHS-IL12

Purpose

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 NHS-IL12 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 NHS-IL12, 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 NHS-IL12 with avelumab intravenous (IV).

Trial Arms

NameTypeDescriptionInterventions
Avelumab and NHS-IL12Experimental
  • Avelumab
  • NHS-IL12

Eligibility Criteria

        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, or subject is intolerant of established therapy known to provide clinical
             benefit for their condition.

          -  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 × the upper limit of normal
                  (ULN) range

               -  Aspartate aminotransferase (AST) levels <= 2.5 × ULN

               -  Alanine aminotransferase (ALT) levels <= 2.5 × ULN

               -  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 the Cockcroft-Gault formula

          -  Negative blood pregnancy test at Screening for women of childbearing potential. For
             the 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, are
             surgically sterile or are sexually inactive.

          -  Highly effective contraception (ie, methods with a failure rate of less than 1% per
             year) must be used before the start of treatment, for the duration of the trial
             treatment, and for at least 60 days after stopping trial participation for both men
             and women if the risk of conception exists. The effects of avelumab and NHS-IL12 on
             the developing human fetus are unknown; thus, women of childbearing potential and men
             must agree to use effective contraception.

        Part B:

          -  Urothelial carcinoma (UC) post-platinum: Histologically or cytologically confirmed
             locally advanced or metastatic transitional cell carcinoma of the urothelium
             (including renal pelvis, ureters, urinary bladder, and urethra). Subjects must have
             progressed after treatment with at least 1 platinum containing regimen for inoperable
             locally advanced or metastatic UC or disease recurrence. 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.

          -  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 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.

          -  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.

          -  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). 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. Subjects must also be willing to undergo an on-treatment
             biopsy procedure.

        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 2 weeks 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 and darbepoetin-α are permitted; Hormonal therapies
                  acting on the hypothalamic-pituitary-gonadal axis are 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 the
                  following exceptions: Subjects with adrenal insufficiency, may continue
                  corticosteroids at physiologic replacement dose, equivalent to less than (<) 10
                  mg prednisone daily; Administration of steroids through a route known to result
                  in a minimal systemic exposure (topical, intranasal, intro-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 the
             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 tuberculosis (history of exposure or history of positive TB (tuberculosis)
                  test with presence of clinical symptoms, physical, or radiographic finding

          -  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.

          -  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
             NHS-IL12 as a part of the manufacturing process)

          -  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 are 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 the opinion of the Investigator might impair the subject's tolerance of trial
             treatment or interpretation of trial results.

          -  Any psychiatric condition that would prohibit the understanding or rendering 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 the exception of acquired
             treatment-related hypogammaglobulinemia requiring periodic IV immunoglobulin infusion.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A and B: Occurrence and Severity of Treatment Emergent Adverse Events (TEAEs) and related TEAEs
Time Frame:Up to 124 Weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Part A: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Area Under the Concentration Time Curve from time of dosing to infinity (AUC0-inf) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Terminal Elimination Rate Constant (λz) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Maximum Serum Concentration (Cmax) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Minimum Serum Concentration (Cmin) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Time to Reach Maximum Concentration Cmax (Tmax) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Apparent Terminal Half-life (t1/2) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: AUC From the Time of Dosing to the Dosing Interval Tau (AUCtau) of Avelumab
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1, 15); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Area Under the Concentration Time Curve from time of dosing to infinity (AUC0-inf) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Terminal Elimination Rate Constant (λz) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Maximum Serum Concentration (Cmax) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Minimum Serum Concentration (Cmin) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Time to Reach Maximum Concentration Cmax (Tmax) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Apparent Terminal Half-life (t1/2) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: AUC From the Time of Dosing to the Dosing Interval Tau (AUCtau) of NHS-IL12
Time Frame:Pre-dose, 1, 4, 8 hours post-infusion (Day 1); Day 2, 3, 8, 11 post-infusion
Safety Issue:
Description:
Measure:Part A: Immunogenicity of Avelumab and NHS-IL12 Measured by ADA Assays
Time Frame:At screening and Pre-dose at Day 15
Safety Issue:
Description:
Measure:Part A: Confirmed Best Overall Response (BOR) According to RECIST v1.1 Criteria
Time Frame:Up to 52 weeks
Safety Issue:
Description:
Measure:Part A: Immune-related BOR Using Immune-related Response Criteria, Derived From RECIST v1.1
Time Frame:Up to 52 weeks
Safety Issue:
Description:
Measure:Part B: Progression Free Survival (PFS) According to RECIST v1.1 Criteria Assessed by Investigator
Time Frame:Baseline until progressive disease or death, assessed up to 124 weeks
Safety Issue:
Description:
Measure:Part B: Overall Survival (OS)
Time Frame:Baseline until death, assessed up to 124 weeks
Safety Issue:
Description:
Measure:Part B: Duration of Response According to RECIST v1.1 Criteria Assessed by Investigator
Time Frame:Baseline until 124 weeks
Safety Issue:
Description:
Measure:Part B: Area Under the Concentration Time Curve from time of dosing to the time of the last observation (AUC0-t) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Area Under the Concentration Time Curve From Time of Dosing to Infinity (AUC0-inf) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Terminal Elimination Rate Constant (λz) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Maximum Serum Concentration (Cmax) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Minimum Serum Concentration (Cmin) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Time to Reach Maximum Concentration Cmax (Tmax) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Apparent Terminal Half-life (t1/2) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: AUC From the Time of Dosing to the Dosing Interval Tau (AUCtau) of Avelumab and NHS-IL12
Time Frame: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)
Safety Issue:
Description:
Measure:Part B: Immunogenicity of Avelumab and NHS-IL12 Measured by ADA Assays.
Time Frame: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)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:EMD Serono Research & Development Institute, Inc.

Trial Keywords

  • Avelumab
  • M9241
  • NHS-IL12
  • Advanced Solid Tumors

Last Updated

August 29, 2017