Date: 2015-04-06
Type of information: Initiation of the trial
phase: 1-2
Announcement: initiation of the trial
Company: Celldex Therapeutics (USA - NJ)
Product: varlilumab, ipilimumab CDX-1401
Action
mechanism: monoclonal antibody/immune checkpoint inhibitor/immunotherapy product. Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs. Varlilumab is currently being studied in three Phase 1/2 combination studies and several additional combination studies will be initiated in 2015. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. Ipilimumab is FDA approved for the treatment of unresectable or metastatic melanoma. CDX-1401 is a next-generation, off-the-shelf cancer vaccine designed to activate the patient's immune system against cancers that express the tumor marker, NY-ESO-1. CDX-1401 consists of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 genetically linked to the NY-ESO-1 tumor antigen. Celldex has accessed NY-ESO-1 through a licensing agreement with the Ludwig Institute for Cancer Research. By selectively delivering the NY-ESO-1 antigen to dendritic cells in the body, CDX-1401 is intended to induce robust immune responses against the antigen-expressing cancer cells.
Disease: unresectable stage III or stage IV melanoma
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: This is a study to determine the clinical benefit, safety and tolerability of combining a) varlilumab and ipilimumab and b) varlilumab, ipilimumab, CDX-1401 and poly-ICLC. The study will enroll patients with unresectable Stage III or Stage IV melanoma. The Phase 1 portion of the study will assess the safety and tolerability of varlilumab at 0.3 and 3.0 mg/kg in combination with ipilimumab at 3 mg/kg administered every three weeks to identify a recommended dose for the Phase 2 portion of the study. The Phase 2 study will include two cohorts—one comprised of patients who are NY-ESO-1 positive and one comprised of patients who are NY-ESO-1 negative. Patients who are NY-ESO-1 positive will also receive CDX-1401 dosed at 1 mg (with poly-ICLC at 2 mg given as an adjuvant) every three weeks in addition to varlilumab and ipilimumab. In total, up to four doses of study treatment will be administered. The primary objective for both cohorts is objective response rate up to 24 weeks (ORR6) using standard, modified World Health Organization response criteria. Secondary objectives for the Phase 2 study include safety and tolerability, immunogenicity, pharmacokinetics and further assessment of anti-tumor activity across a broad range of endpoints. (NCT02413827)
Latest
news: * On April 6, 2015, Celldex Therapeutics announced the initiation of a Phase 1/2 safety pilot and expansion study examining the investigational combination of varlilumab and ipilimumab (Yervoy®; BMS) in patients with Stage III or IV metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, Celldex's off-the-shelf antibody-based dendritic cell vaccine that targets tumors expressing the NY-ESO-1 oncoprotein. The three agents in this study were specifically selected because they uniquely intervene at key points of immune regulation and because Celldex has observed enhanced activity in preclinical studies when varlilumab is combined with either checkpoint inhibitors or with vaccines. In addition, this study will also build on previous clinical data from the CDX-1401 experience that suggests that CDX-1401 may predispose patients to better outcome on checkpoint inhibitors, including ipilimumab.
