A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers

ABSTRACT

Background: Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients.

Methods: 31 Patients received pemetrexed ± cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4⁺ T-cells, with doses tailored to target Treg nadir <4%.

Results: Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. Seventeen percent of patients ceased cyclophosphamide due to toxicity.

Conclusions: Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies.

Trial registration: Clinical trial registration: www.anzctr.org.au identifier is ACTRN12609000260224.

KEYWORDS:

• Malignant mesothelioma
• non-small cell lung cancer
• clinical trial
• phase I
• cyclophosphamide
• immunotherapy
• chemoimmunotherapy

Acknowledgments

This study was supported in by grants from the National Health and Medical Research Council of Australia. The investigators wish to acknowledge the data management staff, in particular Ms Hema Rajandran-Maurel. We also acknowledge the assistance of other research staff in sample processing. The authors acknowledge the facilities, and the scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Centre for Microscopy, Characterization & Analysis, the University of Western Australia; a facility funded by the University, State and Commonwealth Governments.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received institutional grants only for research: Bristol Myers Squibb, Merck, Palobiofarma and Genentech. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Trial conception and design: AKN, RAL, BWSR, MJM

Acquisition of data: AMC, AM, JC, MJM, AH, MM, TM, AKN

Analysis and interpretation of data: AMC, AM, MJM, JC, BWSR, RAL, AKN

Writing, review, and/or revision of manuscript: All authors

Study supervision: AKN, BWSR, MJM

Approval of the final manuscript: All authors.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was supported by the National Health and Medical Research Council of Australia under Grant 572593.