CDX-1307: Clinical Program

A vaccine for hCG-β expressing malignancies

Our first APC Targeting Technology™ product candidate, CDX-1307, is in development for the treatment of cancers that express the beta chain of human chorionic gonadotropin (hCG-β). hCG-β is an established tumor-associated antigen often found in tumors of these types of cancer, but not in most normal tissues. Elevated hCG-β serum levels and/or tissue expansion have been shown to be an independent predictor of disease outcome and are associated with a more aggressive disease course. CDX-1307 is a fusion protein composed of a mannose receptor (MR)-specific human monoclonal antibody and the hCG-β antigen. This antibody-vaccine is designed to deliver the antigen hCG-β to dendritic cells (DCs) and induce hCG-β specific cellular and humoral immune responses, thus activating the patient’s immune system against cancers that express hCG-β. CDX-1307 has been evaluated for the treatment of advanced colorectal, pancreatic, bladder, ovarian and breast cancers in two Phase 1 trials. The Phase 1 data provide the basis for advancing CDX-1307 into a front-line patient population selected for hCG-β expressing cancers. A Phase 2 trial of CDX-1307 (N-ABLE) in the treatment of newly diagnosed bladder cancer is underway.

The N-ABLE Trial (Neoadjuvant and Adjuvant Bladder Cancer Trial)

Open to enrollment
Phase 2: Newly Diagnosed Muscle-Invasive Bladder Cancer Expressing hCG-β
Design	Randomized study of the CDX-1307 vaccine regimen plus neoadjuvant chemotherapy versus neoadjuvant chemotherapy in patients with newly diagnosed, muscle-invasive, hCG-β expressing bladder cancer
Status:	Open to enrollment

CDX-1307: Phase 2 Program

This is a Phase 2 multicenter trial to explore the feasibility and activity of CDX-1307 when given with standard of care chemotherapy and as adjuvant therapy in patients with newly diagnosed, muscle-invasive, hCG-β expressing bladder cancer. Following screening with an hCG-β diagnostic assay, approximately 60 eligible patients will be randomized to receive either a) neoadjuvant gemcitabine and cisplatin chemotherapy, given over three months prior to bladder resection surgery or b) the same neoadjuvant chemotherapy plus the CDX-1307 vaccine regimen, given both neoadjuvantly (prior to surgery) and adjuvantly (following surgery). The CDX-1307 vaccine regimen consists of CDX-1307, given along with the immune stimulators GM-CSF, resiquimod and poly-ICLC over 2-4 days, at 2-4 week intervals for up to six months following surgery, and then at 3 month intervals for an additional six months. The objectives of the study are to evaluate recurrence-free and overall survival during the adjuvant phase, safety, immune response to vaccination, tumor response to neoadjuvant therapy (pathologically from resected tumor specimens and radiographically) and effects of vaccination on the resected tumor, including changes in hCG-β expression.

Patient Eligibility

Among other criteria, patients must meet all of the following conditions to be eligible to be in the study:

18 years of age or older.
Newly diagnosed muscle-invasive transitional cell (urothelial) bladder cancer, where neoadjuvant chemotherapy and radical cystectomy with curative intent are indicated (AJCC stage T2-4a, Nany, M0). Patients must be entered into the study within five weeks of the last procedure (diagnostic biopsy or TURBT).
Histopathologically confirmed, transitional cell (urothelial) carcinoma. Urothelial tumors with mixed histology (but with <50% variant) are eligible.
Tumor tissue (obtained during a prior procedure) confirmed to express hCG-β by a central laboratory.
Candidate for therapy with gemcitabine and cisplatin.

Among other criteria, patients who meet any of the following conditions are NOT eligible to be in the study:

Previous systemic chemotherapy or radiation for bladder cancer (immunotherapy or intravesical [administered within the bladder] chemotherapy for superficial disease is acceptable).
History of anaphylactic reaction following exposure to humanized or human therapeutic monoclonal antibodies, hypersensitivity to GM-CSF or yeast derived products, clinically meaningful allergic reactions to imiquimod, resiquimod, or any known hypersensitivity or prior reaction to any of the formulation excipients in the study drugs.
Concurrent treatment with immunosuppressive or immunomodulatory agents, including any systemic steroid (exception: inhaled or topically applied steroids, and acute and chronic standard dose NSAIDs, are permitted).
Known infection with HIV, HBV or HCV.
Any underlying medical condition that, in the Investigator's opinion, will make the administration of study vaccine hazardous to the patient, would obscure the interpretation of adverse events, or would contraindicate receipt of neoadjuvant chemotherapy or surgical resection.

Please click here for more information about this trial, including a list of clinical trial sites and contact information for prospective patients.

Closed to enrollment
Phase 1: Metastatic or Locally Advanced Cancers
Design	Single arm dose escalation in combination with immune stimulators
Status:	Closed to enrollment

CDX-1307: Phase 1 Program

Celldex has conducted two Phase 1 studies that explore different routes of administration of CDX-1307.

About the Clinical Trials

These trials, which include more than 80 patients, evaluate the safety immune response and biologic activity of CDX-1307 vaccine given alone or with immune stimulators in patients with metastatic or unresectable locally advanced breast, colorectal, pancreatic, ovarian or bladder cancers. Patients are dosed every two weeks for a total of four doses. Initial dose evaluation of CDX-1307 has been followed by evaluation of the vaccine given with immunomodulatory agents (agents that can increase the strength of an immune response). These agents include GM-CSF (a growth factor and stimulator of immune cells), poly-ICLC (Hiltonol™, provided by Oncovir, Inc., a TLR3 agonist and stimulator of immune cells) and resiquimod (a TLR7/8 agonist and stimulator of immune cells provided by 3M).

As presented at the 24th Annual Meeting of the International Society for Biological Therapy of Cancer, the data from these Phase 1 studies have demonstrated enhanced immunological and biological responses in the enrolled patients, who were heavily pre-treated (average of 4.6 prior therapies) and had advanced-stage cancers. All patient cohorts demonstrated a favorable safety profile with no dose limiting toxicity to date. The combination of CDX-1307 with TLR agonists significantly enhanced immune responses against hCG-β, providing strong humoral responses in 88% of patients and cellular immune responses in 57% of patients analyzed to date. Immune responses occurred even in the presence of high circulating levels of hCG-β, suggesting that CDX-1307 can overcome antigen tolerance in advanced and heavily pretreated cancers. Nine patients with breast, colorectal, pancreatic and testicular cancers experienced disease stabilization from 2.3 months to 11.4 months following the initiation of CDX-1307 vaccination. Two of these patients have received multiple courses of CDX-1307 and continue treatment with stable disease at 6.4 and 11.4 months. In order to determine if higher dose impacts immune and clinical responses, an additional cohort combining dual TLR agonists and an increased CDX-1307 dose (15 mg) has also been enrolled (data are pending).