E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Dose escalation: lung, colon, kidney, skin
Dose expansion: lung, cutaneous melanoma, uveal melanoma, liver, gastroesophageal, pancreatic adenocarcinoma, head and neck, triple neg. breast, bladder |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Dose-escalation phase: to determine the maximum tolerated dose (MTD) or optimal biological dose (OBD), and the safety profile of MEDI4736 in subjects with advanced solid tumors.
Dose-expansion phase:
1. To determine the safety profile of MEDI4736 in subjects with advanced cutaneous melanoma, uveal melanoma, hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck (SCCHN), NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, triple negative breast cancer (TNBC), pancreatic adenocarcinoma, urothelial cancer (UBC) etc (Refer to protocol section 2.1 for more information).
2. To evaluate the antitumor activity of MED14736 in subjects with non-squamous NSCLC who have received 2 or more prior lines of therapy and subjects with squamous NSCLC who have received 1 prior line of therapy and 2 or more prior lines of therapy.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study follow:
1) To describe the pharmacokinetics (PK) of MEDI4736
2) To determine the immunogenicity (IM) of MEDI4736
3) To evaluate the antitumor activity of MEDI4736 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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 therapy cohorts will be required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.
Age ≥ 18 years at time of study entry.
Effective contraception (refer to protocol for further details).
Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
Adequate organ and marrow function.
Subjects must have at least 1 measurable lesion per RECIST v1.1
guidelines or per RANO guidelines for subjects with GBM.
Available unstained archived tumor tissue sample (for subjects in the
UBC cohort who provide a fresh tumor biopsy, additional archival tissue is required).
Life expectancy ≥ 16 weeks
At least 1 lesion amenable to biopsy (dose-expansion phase only).
Willingness to provide consent for biopsy samples (dose-expansion phase only).
Histologically/cytologically confirmed advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous and nonsquamous histology, gastroesophageal cancer, TNBC, or pancreatic adenocarcinoma (dose-exploration cohort). |
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E.4 | Principal exclusion criteria |
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose-escalation phase: evaluation of DLTs (dose-limiting toxicity),
overall safety, and parameters related to the MTD (maximum tolerated dose) or OBD (optimal biological dose). The MTD evaluation will be based on the DLT Evaluable Population. The OBD will be determined based upon analysis of all available subject data, including safety, pharmacokinetic, pharmacodynamic, biomarker, and response data.
Dose-expansion phase:
Endpoints for safety profile - assessments of AEs, SAEs, laboratory
evaluations, vital signs, and physical examinations.
The primary endpoint for of the antitumor activity for the NSCLC and UBC cohorts is objective response (OR), which is defined as a best overall response (BoR) of CR or PR according to RECIST v1.1 as determined by BICR. BoR is defined as the best response (in the order of CR, PR, SD, PD, and not evaluable) among all overall responses recorded from the start of treatment until objective documentation of PD (per RECIST v1.1 as assessed by BICR), or the last evaluable disease assessment in the absence of PD prior to initiation of subsequent anticancer therapy or discontinuation from the study, whichever occurs first.
The primary endpoint for UBC cohort in PD-L1-positive subgroup is
considered to be met if the lower-limit of the exact 2-sided 95% CI for ORR excludes a historical response rate of 10% or less. ORR per BICR for the UBC cohort will be repeated for UBC subjects in PD-L1-positive FAS, PD-L1 negative FAS and FAS (regardless of PD-L1 status) enrolled in the entire study.
For the dose-exploration cohort, the primary objective is to determine the safety profile of MEDI4736 in subjects with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC and pancreatic adenocarcinoma using a Q4W dosing schedule.
Endpoints for safety profile including assessments of AEs, SAEs,
laboratory evaluations, vital signs, and physical examinations will be
summarized in the same manner as those described above for doseexpansion phase. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Continous through to 90 days after the last dose of MEDI4736
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E.5.2 | Secondary end point(s) |
1. Assessment of Pharmacokinetics
2. Assessment of Immunogenicity
3. Assessment of Antitumour activity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 90 days after the last dose of MEDI4736
2.Up to 6 months after the last dose of MEDI4736
3. Tumour efficacy evaluations and survivial status continue until
withdrawal of consent or death. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 16 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
France |
Germany |
Italy |
Korea, Republic of |
Netherlands |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study (“study completion”) is defined as the date of the last protocol-specified visit/assessment (including telephone contact) for the last subject in the study or the date the study is closed by the sponsor, which ever occurs first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |