Overview

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

Status:
Terminated
Trial end date:
2020-10-08
Target enrollment:
0
Participant gender:
All
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).
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
EMD Serono
EMD Serono Research & Development Institute, Inc.
Collaborators:
Merck KGaA
Merck KGaA, Darmstadt, Germany
Treatments:
Antibodies, Monoclonal
Avelumab
Immunoglobulin G
Interleukin-12
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, 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.