Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.

Abstract

PURPOSE:

The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.

PATIENTS AND METHODS:

Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response.

RESULTS:

Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment.

CONCLUSION:

The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.

• Authors: Robert H Vonderheide, Keith T Flaherty, Magi Khalil, Molly S Stumacher, David L Bajor, Natalie A Hutnick, Patricia Sullivan, J Joseph Mahany, Maryann Gallagher, Amy Kramer, Stephanie J Green, Peter J O'Dwyer, Kelli L Running, Richard D Huhn, Scott J Antonia
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 25 Issue 7 Pg. 876-83 (Mar 01 2007) ISSN: 1527-7755 [Electronic] United States
• PMID: 17327609 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• CD40 Antigens
• Cytokines
• selicrelumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• CD40 Antigens (agonists)
• Cytokines (metabolism)
• Dose-Response Relationship, Drug
• Female
• Humans
• Liver (drug effects)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, immunology)