A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects with Advanced Solid Tumors
- Conditions
- Advanced Solid TumorsTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2012-002206-52-GB
- Lead Sponsor
- MedImmune
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 1322
Written informed consent.
Dose-escalation phase: histologically-or cytologically- confirmed
advanced melanoma, renal cell carcinoma, non-small cell lung cancer, or colorectal cancer that is refractory to standard therapy and for which no standard therapy exists.
Dose-expansion phase: histologically-or cytologically-confirmed
advanced utaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous and non-squamous, gastroesophageal cancer, TNBC, or pancreatic adenocarcinoma, urothelial bladder cancer, GBM, epithelial ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, HPV-positive cancers, or nasopharyngeal carcinoma.
HCC subjects must be of Child-Pugh class A (not amenable to or
refractory to locoregional therapy). Subjects with HCC associated with hepatitis B virus must be receiving adequate antiviral therapy.
Subjects with histologically or cytologically confirmed inoperable or metastatic transitional cell carcinoma of the urothelium (subjects must have received and have progressed or are refractory to at least 1 but not more than 2 prior lines of systemic therapy for inoperable or metastatic disease)
Subjects with histologically or cytologically documented NSCLC must
present with Stage IIIB/ Stage IV disease, or with recurrent or progressive disease following multimodal therapy for locally advanced disease (refer to protocol for further details).
Subjects with SCCHN must have disease that is either metastatic or
recurrent and deemed to be incurable by the investigator.
MSI-high cancers must have defective DNA mismatch repair by EITHER high-frequency microsatellite instability with changes detected in 2 or more panels of microsatellite markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) OR immunohistochemical analysis demonstrating
absence of protein expression of any 1 or more of the following proteins: MLH1, MSH2, MSH6, PMS2.
Subjects with HPV-positive cancers are eligible if they have a confirmed HPV positive tumor by local laboratory.
GBM cohort: Subjects with GBM must not have significant edema or shift from midline by intracranial imaging, or be symptomatic due to edema. A minimum of 10 subjects without O6-methylguanine-DNA
methyltransferase promoter methylation will be enrolled in the GBM
cohort
Epithelial ovarian cancer cohort: A minimum of 10 subjects with
platinum sensitivity will be enrolled in the ovarian cancer cohort
If an approved first-line standard therapy is available, subjects must have failed, be intolerant to, be ineligible for, or have refused treatment.
Progressive disease as assessed by the investigator or treatment naïve at the time of study entry.
Tumoral PD-L1 expression requirements are as follows:
·HCC, gastroesophageal cancer, TNBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, HPV-positive cancers, pancreatic adenocarcinoma, and nasopharyngeal carcinoma dose-expansion cohorts: after the first 20-40 subjects in each cohort are enrolled, additional subjects in the applicable cohorts may be required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.
NSCLC (squamous and non-squamous) dose-expansion cohorts:
Non-squamous NSCLC: all remaining subjects to be enrolled will be required to have tumoural PD-L1 expression as determined by prospective testing prior to enrollement.
Squamous NSCLC: a minimum of 10 subjects in the first-line therapy cohort, and a minimum of 35 subjects in each of the second-line therapy and third-line or greater
Concurrent enrollment in another clinical study, unless it is an
observational (non-interventional) clinical study or the follow-up period of an interventional study.
Receipt of any immunotherapy, BRAF inhibitor (in cutaneous melanoma and uveal melanoma subjects), or investigational anticancer therapy within 4 weeks prior to the first dose of MEDI4736; in the case of MAbs, 6 weeks prior to the first dose of
MEDI4736.
Any prior Grade = 3 irAE while receiving immunotherapy.
For all subjects: prior exposure to any anti-PD-1 or anti-PD-L1 antibody.
For UBC cohort: prior treatment with immunotherapy agents including, but not limited to, tumor necrosis factor receptor superfamily agonists or checkpoint inhibitors or natural killer (NK) cell inhibitors including agents targeting KIR, PD-1, PD-L1, CTLA-4, OX40, CD27, CD137 (4-1BB), CD357 (GITR), and CD40. Prior treatment with Bacillus Calmette-Guerin therapy is permitted.
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736.
Active or prior documented autoimmune disease within the past 2 years
NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
History of primary immunodeficiency.
History of organ transplant that requires use of immunosuppressives.
Known allergy or reaction to any component of the MEDI4736
formulation.
Untreated CNS metastatic disease, leptomeningeal disease, or cord
compression.
Other invasive malignancy within 2 years except for noninvasive
malignancies that have been surgically cured.
Unresolved toxicities from prior anticancer therapy.
Major surgical procedure (as defined by the investigator) within 30 days prior to the first dose of MEDI4736 or still recovering from prior surgery.
Females who are pregnant or lactating.
Uncontrolled intercurrent illness.
Any condition that would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
Known history of tuberculosis.
Known to be human immunodeficiency virus (HIV) positive.
Hepatitis B or C infection.
Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736.
Subjects with pancreatic adenocarcinoma must not have more than 50% of the liver parenchyma replaced by tumour.
Subjects with HCC must not have a history of bleeding from esophageal varices, unless the varices have been treated with no active bleeding within 30 days prior to the first dose of MEDI4736.
Prior participation in clinical studies that include MEDI4736 alone or in combination, where the study has registrational intent and the analyses for the primary endpoint have not yet been completed.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method