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
- Cancersolid tumors10027655
- Registration Number
- NL-OMON48631
- Lead Sponsor
- Merck KGaA
- Brief Summary
Trial ended prematurely
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 7
UrothelialSigned written informed consent
2. Male or female subjects age * 18 years
3. Subjects must have one of the following tumor specific indications:
-a. Locally advanced or metastatic urothelial carcinoma (UC) post-that has
progressed during or after at least one platinum:-based chemotherapy and not
previously been treated with anti-PD-1/PD-L1 agents (PD-x naïve):
Histologically or cytologically confirmeddocumented locally advanced or
metastatic transitional cell carcinoma of the urothelium (including renal
pelvis, ureters, urinary bladder, and urethra). Subjects must have progressed
during or after treatment with at least 1 platinum -containing regimen (eg,
platinum plus another agent such as gemcitabine, methotrexate, vinblastine,
doxorubicin, etc) for inoperable locally advanced or metastatic UC or disease
recurrence. Availability of either tumor archival material or fresh
biopsiesSubjects who received prior adjuvant/neoadjuvant chemotherapy and
progressed within 28 days is acceptable12 months of treatment with one of these
being mandatory. For FFPE samples, either block or sections (> 15) maya
platinum-containing regimen will be provided. Tumor biopsies and tumor archival
material must be suitable for biomarker assessment.considered as second line.
Subjects with mixed histologies are required to
have a dominant transitional cell pattern
b. Non-small cell lung cancer, first-line metastatic: Histologically proven
Stage IV (per seventh International Association for the Study of Lung Cancer
classification) 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 / rearrangement 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
FDA-approved PD-L1 test. This cohort will not be opened for enrollment in
Belgium, Czech Republic, France, Germany,
Hungary, Italy,
Netherlands, Spain, and United Kingdom
c. Colorectal cancer, second line or later: 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
MSI-low or MSS metastatic CRC are eligible.
Subjects without existing MSI test results will have MSI status
- performed locally by a CLIA-certified IHC or PCR-based test
(PCRbasedPCR-based MSI test is preferred). Subjects must be willing to undergo
an ontreatment biopsy procedure. For Belgium, Czec
1. Concurrent treatment with a non-permitted drug/intervention (listed below)
a. 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 study treatment, or not recovered from adverse
events (AE) related to such therapies, with the following exceptions:
i. Palliative radiotherapy delivered in a normal organ-sparing technique is
permitted (concurrently or within pretreatment period).
ii. Erythropoietin, darbepoetin-*, and granulocyte colony-stimulating factor
are permitted.
iii. Hormonal therapies acting on the hypothalamic pituitary gonadal axis are
permitted (ie, luteinizing hormone releasing hormone agonist/antagonists). No
other hormonal anticancer therapy is permitted.
b. Major surgery (as deemed by Investigator) for any reason (except diagnostic
biopsy) within 4 weeks prior to start of study treatment, or not fully
recovered from surgery within 4 weeks prior to start of study treatment
c. Subjects receiving immunosuppressive agents (such as steroids) for any
reason should be tapered off these drugs before start of study treatment, with
the following exceptions:
i. Subjects with adrenal insufficiency, may continue corticosteroids at
physiologic replacement dose, equivalent to * 10 mg prednisone daily.
ii. Administration of steroids through a route known to result in a minimal
systemic exposure (topical, intranasal, intra-ocular, or inhalation) is
permitted.
iii. 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.
2. Any prior treatment with any form of IL-12
3. 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
4. Intolerance to checkpoint inhibitor therapy, as defined by the occurrence of
an AE requiring drug discontinuation.
5. Active or history of primary or metastatic central nervous system tumors
6. Prior organ transplantation, including allogeneic stem cell transplantation
7. Previous malignant disease (other than the indication for this study) within
the last 5 years (except adequately treated nonmelanoma 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 study entry and the subject was deemed to have been cured with no
additional therapy required or anticipated to be required.
8. Significant acute or chronic infections requiring systemic therapy
including, among others:
a. History of testing positive test for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome
b. Hepatitis B or C infection (HBV surface antigen positive and HBV core
antibody positive with reflex to positive HBV DNA or HBV core antibody positive
alone with reflex to positive HBV DNA or positiv
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary endpoints:<br /><br>* Confirmed best overall response (BOR) by Investigator assessment according to<br /><br>RECIST v1.1 by selected tumor type<br /><br>* Occurrence, severity, and duration of TEAEs and TRAEs, graded according to<br /><br>the NCI CTCAE v4.03.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary endpoints:<br /><br>* Progression-free survival (PFS) time<br /><br>* Overall survival (OS) time<br /><br>* Duration of response (DOR)<br /><br>* PK profiles of avelumab and M9241<br /><br>* Immunogenicity of avelumab and immunogenicity of M9241 in combination<br /><br>therapy, as measured by ADA assays.<br /><br>Exploratory endpoints:<br /><br>* irBOR using the irRECIST<br /><br>* immune-related PFS (irPFS) using the irRECIST<br /><br>* Change from baseline of PRO disease-related symptoms and physical functioning<br /><br>concepts from the European Organisation for Research and Treatment of Cancer<br /><br>(EORTC) item bank.</p><br>