A Study of CDX-1140 (CD40) as Monotherapy or in Combination in Patients With Advanced Malignancies

Sponsor

Celldex Therapeutics (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03329950

Collaborator

Merck Sharp & Dohme LLC (Industry)

132

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a study to determine the maximum tolerated dose (MTD) for CDX-1140 (CD40 antibody), either alone or in combination with CDX-301 (FLT3L), pembrolizumab, or chemotherapy and to further evaluate its tolerability and efficacy in expansion cohorts once the MTD is determined.

Condition or Disease	Intervention/Treatment	Phase
Melanoma Non-small Cell Lung Cancer Breast Cancer Gastric Cancer Renal Cell Carcinoma Ovarian Cancer Cholangiocarcinoma Bladder Urothelial Carcinoma Pancreatic Adenocarcinoma Colorectal Cancer Esophageal Cancer Hepatic Cancer Head and Neck Cancer Primary Peritoneal Cancer Fallopian Tube Cancer Other Solid Tumors Diffuse Large B-cell Lymphoma (DLBCL) Mantle Cell Lymphoma Indolent B-cell Lymphomas Non-Hodgkin Lymphoma Follicular Lymphoma Lymphoplasmacytic Lymphoma Waldenstrom's Disease Marginal Zone Lymphoma Mucosa Associated Lymphoid Tissue Small Lymphocytic Leukemia	Drug: CDX-1140 Drug: CDX-301 Drug: Pembrolizumab Drug: Chemotherapy	Phase 1

Detailed Description

This study will determine the MTD of CDX-1140 while also evaluating the safety, tolerability and efficacy of CDX-1140 alone (Part 1) or in combination with CDX-301 (Part 2), pembrolizumab (Part 3), or chemotherapy (Part 4) in patients with cancer.

Eligible patients that enroll to the dose-escalation portion of the study will be assigned to one of several dose levels of CDX-1140. The dose-escalation part of the study will test the safety profile of CDX-1140, alone or in combination with CDX-301, pembrolizumab or chemotherapy and determine which dose(s) of CDX-1140 will be studied in the expansion portions of the study.

All patients enrolled in the study will be closely monitored to determine if there is a response to the treatment as well as for any side effects that may occur.

Study Design

Study Type:

Interventional

Actual Enrollment :

132 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Study of CDX-1140 as Monotherapy or in Combination in Patients With Advanced Malignancies

Actual Study Start Date :

Dec 1, 2017

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CDX-1140 Part 1: Eligible patients will receive CDX-1140, based on cohort assigned, in 4 week cycles until progression, intolerance, or two years of treatment.	Drug: CDX-1140 CDX-1140 will be administered every 4 weeks in Parts 1, 2 and 4, and every 3 weeks in Part 3.
Experimental: CDX-1140 and CDX-301 Part 2: Eligible patients will receive CDX-1140, based on cohort assigned, in 4 week cycles until progression, intolerance or two years of treatment. A fixed dose of CDX-301 is injected once a day for five days before cycles 1 and 2 of CDX-1140.	Drug: CDX-1140 CDX-1140 will be administered every 4 weeks in Parts 1, 2 and 4, and every 3 weeks in Part 3. Drug: CDX-301 CDX-301 will be injected once a day for five days before Cycles 1 and 2.
Experimental: CDX-1140 and pembrolizumab Part 3: Eligible patients will receive CDX-1140, based on cohort assigned, in 3 week cycles until progression, or intolerance, or two years of treatment. A fixed dose of pembrolizumab will also be given in 3 week cycles.	Drug: CDX-1140 CDX-1140 will be administered every 4 weeks in Parts 1, 2 and 4, and every 3 weeks in Part 3. Drug: Pembrolizumab Pembrolizumab will be administered every 3 weeks.
Experimental: CDX-1140 and chemotherapy Part 4: Eligible patients will receive CDX-1140, based on cohort assigned, in 4 week cycles until progression, or intolerance, or two years of treatment. Chemotherapy will also be given according to standard of care.	Drug: CDX-1140 CDX-1140 will be administered every 4 weeks in Parts 1, 2 and 4, and every 3 weeks in Part 3. Drug: Chemotherapy Gemcitabine and Nab-paclitaxel will be administered on Day 1, Day 8 and Day 15 of each 4 week Cycle.

Outcome Measures

Primary Outcome Measures

Safety and Tolerability of CDX-1140 as assessed by CTCAE v5.0 [From first dose through 30 days after last dose]
The rates of drug-related adverse events will be summarized and maximum tolerated dose will be determined.

Secondary Outcome Measures

Objective Response Rate [Every 8-12 weeks, starting with first dose until disease progression, assessed up to approximately 1-3 years.]
The percentage of patients who achieved a confirmed complete response or partial response by evaluation criteria in solid tumors for immune-based therapeutics (iRECIST; for solid tumor patients) and the lymphoma response to immunomodulatory therapy criteria (LYRIC; for lymphoma patients).
Clinical benefit rate [Every 8-12 weeks, starting with first dose until disease progression, assessed up to approximately 1-3 years]
The percentage of patients who achieve best response of confirmed CR or PR, or stable disease (SD) for at least four months
Duration of Response [First occurrence of a documented objective response to disease progression or death (up to approximately 1-3 years)]
The interval from which measurement criteria are first met for CR or PR until the first date that progressive disease is objectively documented
Progression-free survival [From first dose to the first occurrence of disease progression or death due to any cause (up to approximately 1-3 years)]
The time from start of study drug to time of progression or death, whichever occurs first
Overall survival [The time from start of study drug to death from any cause (up to approximately 1-3 years)]
The time from start of study drug to death
Immunogenicity evaluation [Prior to each dose of study treatment and at treatment discontinuation, up to approximately 1-3 years]
Serum samples will be obtained for assessment of human anti-CDX-1140 and anti-CDX-301 antibodies
Pharmacokinetic evaluation [Prior to each study treatment, multiple timepoints after each study treatment, and at treatment discontinuation up to approximately 1-3 years]
CDX-1140 and CDX-301 concentrations will be measured

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Recurrent, locally advanced or metastatic melanoma (including mucosal and/or ocular), bladder/urothelial, non-small cell lung cancer, pancreatic adenocarcinoma, breast, colorectal, gastric, esophageal, renal cell, hepatic, ovarian fallopian or primary peritoneal carcinoma, head and neck, and cholangiocarcinoma. Additional tumor types (except primary CNS tumors) may be enrolled after discussion with, and approval from, the medical monitor.
Must have received all standard of care therapies (approved or unapproved) as deemed appropriate by the treating physician. Patients who refuse standard therapy are excluded from the study.
If of childbearing potential (male or female), agrees to practice an effective form of contraception during study treatment and for at least 3 months following last treatment
Willingness to undergo a pre-treatment and on-treatment biopsy, if required.

Additional Inclusion Criteria for Part 1:

Advanced diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, or indolent B-cell lymphoma are also eligible.
Lymphoma patients must have received ≥ 1 prior systemic therapy

Additional Inclusion Criteria for Part 3:

Patients must have documented progression while receiving anti-PD-1 or anti-PD-L1 based regimens for FDA approved indications
Patients cannot have received more than one anti-PD-1 or anti-PD-L1 based regimen

Additional Inclusion Criteria for Part 4:

Patients must have metastatic pancreatic adenocarcinoma, and have not received previous treatment in a metastatic setting

Key Exclusion Criteria:

History of severe hypersensitivity reactions to other monoclonal antibodies.
Previous treatment with any anti-CD40 antibody or with FLT3L.
Inadequate washout period from prior therapy as defined in the Protocol.
Major surgery within 4 weeks prior to study treatment.
Use of immunosuppressive medications within 4 weeks or systemic corticosteroids within 2 weeks prior to study treatment.
Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or in situ cancers. For all other cancers, the patient must be disease-free for at least 3 years to be allowed to enroll.
Active, untreated central nervous system metastases.
Active autoimmune disease or documented history of autoimmune disease.
History of (non-infectious) pneumonitis or has current pneumonitis.
Active infection requiring systemic therapy, known infection of HIV, Hepatitis B, or Hepatitis C.

Additional Exclusion Criteria for lymphoma patients in Part 1:

Prior allogenic stem cell transplantation
Patients who have received autologous stem cell transplant ≤ 12 weeks prior to the first dose of study drug.

There are additional criteria your study doctor will review with you to confirm your eligibility for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth Research Insititute	Scottsdale	Arizona	United States	85258
2	Northside Hospital, Inc.	Atlanta	Georgia	United States	30342
3	Georgia Cancer Center at Augusta University	Augusta	Georgia	United States	30912
4	Oncology Hematology West, PC dba Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
5	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Gabrail Cancer Center Research LLC	Canton	Ohio	United States	44718
8	Providence Portland Medical Center	Portland	Oregon	United States	97213
9	Abramson Cancer Center at the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
10	Rhode Island Hospital (RIH) The Miriam Hospital (TMH)	Providence	Rhode Island	United States	02903
11	Houston Methodist	Houston	Texas	United States	77030