A Multiple Ascending Dose Study of MEDI7247 in Advanced or Metastatic Solid Tumors

Study Overview
=================
Brief Summary
-----------------
To assess safety and tolerability, describe the dose-limiting toxicities, assess the preliminary antitumor activity, determine the maximum tolerated dose (MTD) or the highest protocol-defined dose (maximum administered dose) in the absence of establishing the MTD, and a recommended dose for further evaluation of MEDI7247 in patients with selected advanced or metastatic solid tumor malignancies that have received at least 1 prior line of treatment.

Official Title
-----------------
A Phase 1/1b Multicenter, Open-label, Dose-escalation, and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI7247 in Patients With Advanced or Metastatic Disease in Selected Solid Tumors

Conditions
-----------------
Non Small Cell Lung Cancer Squamous (NSCLC-Sq), Head and Neck Squamous Cell Carcinoma (HNSCC), Small Cell Lung Cancer (SCLC), Pancreatic Ductal Adenocarcinoma (PDAC), Colorectal Cancer (CRC), Metastatic Castration-resistant Prostate Cancer (mCRPC)

Intervention / Treatment
-----------------
* Drug: MEDI7247


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of advanced or metastatic select solid tumors and either progression on or documented intolerance to standard therapies Age ≥ 18 years at the time of screening. Written informed consent and any locally required authorization Eastern Cooperative Oncology Group (ECOG) performance status 0-1 At least 1 measurable target lesion by CT or MRI per RECIST Version 1.1 (excluding mCRPC) Adequate Liver Function: Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 × ULN (upper limit normal), Albumin > 3 g/dL, and serum total bilirubin (TBL) ≤ 1.5 × ULN; (unless bilirubin rise is due to Gilbert's syndrome, hepatic metastases or of non-hepatic origin, in which case TBL ≤ 3 × ULN is allowed) Creatinine Clearance (CrCL) ≥ 40 mL/min Adequate Hematopoesis: Absolute Neutrophil Count (ANC) ≥ 1,500/μL, Platelets ≥ 100,000/μL, and Hgb ≥ 9 g/dL unassisted by transfusion or growth factor within 14 days of screening Provision of archival or fresh tumor tissue at screening Female patients of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception, and must agree to continue using such precautions for 90 days after the last dose of investigational product. Nonsterilized male patients who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from 7 days post-screening and for 90 days after receipt of the last dose of investigational product. Exclusion Criteria: Active central nervous system (CNS) metastases, unless adequately treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) and prednisolone 10 mg or less for more than 2 weeks prior to enrollment. For SCLC, a brain MRI scan that was conducted ≤ 28 days from Day 1 is required. Residual toxicity from prior anticancer therapy not resolved to NCI CTCAE v4.03 Grade 1, with the exception of alopecia/vitiligo at the time of first dose of investigational product. For patients previously receiving immunotherapy, toxicities that are unlikely to recover to Grade 1. Royal Marsden Hospital (RMH) prognostic score 2 and 3 at baseline. Treatment with anticancer therapy including chemotherapy, radiation therapy, immunotherapy, biologic, or any investigational therapy within 21 days, or prior palliative radiotherapy within 2 weeks of the first dose of investigational product. 5 Prior treatment with other Pyrrolobenzodiazepine-Antibody Drug Conjugates. 6 History of previous malignancies (except for locally curable cancers) unless a complete remission was achieved at least 3 years prior to study entry AND no additional therapy is required during the study period (except adjuvant hormonal therapy and bisphosphonate). 7. Failure to recover from major surgery or significant traumatic injury within 21 days of first dose of study treatment. 8 History of hepatic sinusoidal obstruction syndrome, also called veno-occlusive disease 9. History of capillary leak syndrome. 10 Blood transfusion within 14 days of study entry except when needed for disease related anemia. 11. New York Heart Association classes III-IV congestive heart failure or serious cardiac arrhythmia requiring treatment, history of myocardial infarction, unstable angina, vascular stent, or coronary artery bypass graft within 6 months of the first dose of investigational product. 12. Active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infections at the time of screening. 13. Current severe active systemic disease including active concurrent malignancy 14. Pregnancy and/or breastfeeding at time of screening 15. Concurrent enrollment in anther clinical study involving an investigational treatment that is not an extension of another MedImmune study with the same investigational product.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 101 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NSCLC-Sq/HNSCC<br>Patients with advanced or metastatic NSCLC-Sq or HNSCC who have recurrence after, or are refractory or intolerant to standard therapy, including at least one prior standard of care regimen (platinum-based for HNSCC). PDL-1 positive patients should have received previous PD-1 or PD-L1 inhibitor where available. | Drug: MEDI7247<br>* Subjects with advanced solid tumors will enroll into the respective arms to receive Medi7247 IV at prescribed dose and schedule<br>|
| Experimental: Small Cell Lung Cancer<br>Patients with advanced SCLC who have recurrence after, or are refractory or intolerant to standard therapy, including at least one prior standard of care regimen. | Drug: MEDI7247<br>* Subjects with advanced solid tumors will enroll into the respective arms to receive Medi7247 IV at prescribed dose and schedule<br>|
| Experimental: Colorectal Cancer<br>Patients with metastatic adenocarcinoma of the colon or rectum who have received and have progressed, or have documented intolerance, on prior thymidylate synthase inhibitor (eg, 5-fluorouracil (5-FU), capecitabine, raltitrexed, tegafur-uracil (UFT), irinotecan, and oxaliplatin for metastatic disease. If patients progress within 6 months of their last dose of adjuvant therapy this should be considered as a line of therapy in the metastatic setting. Patients with known RAS wildtype tumors must have received and progressed, or have documented intolerance, on anti-EGFR antibody. Patients with microsatellite instability-high or deficient mismatch repair tumors, must have received and progressed, or have documented intolerance on a PD-1 inhibitor, or PD-1 inhibitor plus cytotoxic T-lymphocyte antigen-4 inhibitor treatment where available. | Drug: MEDI7247<br>* Subjects with advanced solid tumors will enroll into the respective arms to receive Medi7247 IV at prescribed dose and schedule<br>|
| Experimental: Pancreatic Ductal Adenocarcinoma<br>Patients with unresectable, locally advanced or metastatic PDAC who have recurrence after, or are refractory or intolerant to standard therapy, including at least one prior line of treatment. | Drug: MEDI7247<br>* Subjects with advanced solid tumors will enroll into the respective arms to receive Medi7247 IV at prescribed dose and schedule<br>|
| Experimental: Metastatic Castration-Resistant Prostate Cancer<br>Patients with mCRPC who have received prior treatment with abiraterone or enzalutamide, with or without a prior taxane-based chemotherapy in the mCRPC setting. | Drug: MEDI7247<br>* Subjects with advanced solid tumors will enroll into the respective arms to receive Medi7247 IV at prescribed dose and schedule<br>|
| Experimental: Other advanced/metastatic target expressing solid tumors<br>Patients with advanced or metastatic solid tumors not defined by other treatment arms who have positive expression of the protein target and have exhausted all approved therapies | Drug: MEDI7247<br>* Subjects with advanced solid tumors will enroll into the respective arms to receive Medi7247 IV at prescribed dose and schedule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events | To assess the occurrence of adverse events | From time of informed consent through 90 days post end of treatment | 
| Occurrence of Serious Adverse Events | To assess the occurrence of serious adverse events | From time of informed consent through 90 days post end of treatment | 
| Occurrence of Dose Limiting Toxicities | To assess the occurrence of toxicities and abnormal laboratory results that may limit further dose administration | During the evaluation period of 21 days post first dose | 
| Number of patients with changes in laboratory parameters from baseline | To assess serum chemistry, hematology, urinalysis and coagulation parameters | From time of informed consent through 90 days post end of treatment | 
| Number of patients with changes in vital signs parameters from baseline | to assess changes in vital signs | from time of informed consent through 21 days post last dose | 
| Number of patients with changes in electrocardiogram results from baseline | to assess changes in ECG | from time of informed consent through 21 days post last dose | 
| Percentage of patients with changes in laboratory parameters from baseline | to assess changes in serum chemistry, hematology, urinalysis, and coagulation parameters | from time of informed consent through 90 days post end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MEDI7247 maximum observed concentration (Cmax) | To characterize MEDI7247 single agent Pharmacokinetics | From first dose through 90 days post end of treatment | 
| MEDI7247 terminal half life (t1/2) | To characterize single agent MEDI7247 pharmacokinetics | From first dose through 90 days post end of treatment | 
| MEDI7247 area under the concentration/time curve (AUC) | To characterize single agent MEDI7247 pharmacokinetics | from first dose through 90 days post end of treatment | 
| MEDI7247 clearance | to characterize the single agent MEDI7247 pharmacokinetics | from first dose through 90 days post end of treatment | 
| Number of subjects who develop anti-drug antibodies | To characterize MEDI7247 immunogenicity | first dose through 90 days post end of treatment | 
| Best Overall Response | To assess antitumor activity of MEDI7247 | From time of informed consent and up to 90 days post end of treatment | 
| Objective Response Rate (ORR) | To assess antitumor activity of MEDI7247 | From time of informed consent and up to 2 years after last subject in | 
| Time to Response (TTR) | To assess antitumor activity of MEDI7247 | From time of informed consent and up to 90 days post end of treatment | 
| Duration of Response (DoR) | To assess antitumor activity of MEDI7247 | From time of informed consent and up to 2 years after last subject in | 
| Progression Free Survival (PFS) | To assess the antitumor activity of MEDI7247 | From time of informed consent and up to 2 years after last subject in | 
| Disease Control (DC) | To assess antitumor activity of MEDI7247 | From time of informed consent and up to 2 years after last subject in | 
| Overall Survival (OS) | To assess antitumor activity of MEDI7247 | From time of informed consent and up to 2 years after last subject in | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Medi7247, non small cell lung cancer, head and neck cancer, small cell lung cancer, colorectal cancer, prostate cancer, pancreatic adenocarcinoma