Durvalumab in Combination With Chemotherapy in Treating Patients With Advanced S

Durvalumab in Combination With Chemotherapy in Treating Patients With Advanced Solid Tumors, (DURVA+ Study)

https://clinicaltrials.gov/ct2/show/NCT03907475?term=NCT03907475&draw=2&rank=1

Evaluation of T-cell activation in refractory biliary cancers treated with

gemcitabine and checkpoint inhibition

Significance and Background:

The objective of the proposed study is to examine the effects of gemcitabine on immune activation and tumor antigenicity in refractory biliary cancers when used in combination with the PDL-1 inhibitor durvalumab. We propose that gemcitabine will elicit increased tumor antigenicity (i.e., TMB and/or MSI) and will trigger a greater activation of T-cells when combined with durvalumab in comparison with durvalumab alone.

Our detailed investigative approach will identify mechanisms to increase treatment response to ICIs when used in combination with gemcitabine in refractory biliary cancers. We expect that chemotherapy will increase tumor antigenicity (i.e., TMB and MSI) and potentially trigger response to ICI therapy. [1, 2] We will be studying the degree of T-cell activation in response to gemcitabine, which would serve as a marker for immune activation and as a marker for the efficacy of ICI therapy. We will be assessing T-cell activation, TMB and MSI using assays that were developed by our collaborators at the Frederick National Laboratory for Cancer Research. The results from this study would provide preliminary clinical data and proof of concept of increased immune activation, which could potentially result in increased clinical response. With these preliminary data, we anticipate opening an expansion cohort of the gemcitabine and durvalumab combination arm in refractory biliary tumors to confirm these findings and assess response. Thus, the results of this study will have broad and immediate clinical relevance to the treatment of refractory biliary cancers.

Approach:

The proposed study will be performed using biopsy samples from patients with refractory biliary cancers on the “DURVA+: Evaluation of the Safety and Pharmacodynamics of Anti-PD-L1 Antibody MEDI4736 (durvalumab) in Combination with Chemotherapy in Patients with Advanced Solid Tumors” clinical trial (NCT03907475) This large clinical trial evaluates durvalumab, either alone or in combination with 6 different chemotherapeutic agents. The trial enrolls adult patients with advanced solid tumors who have progressed on at least one line of standard therapy (or have tumors for which no standard treatment exists).  Patients will be placed onto one of 7 treatment arms (Figure 1) in an unblinded fashion and assignment will determined by the PI or study chair based on histology and prior systemic therapy.

Patients having received prior anti-PD1/PDL-1  will be eligible for arms 2-7. Patients who have not received prior anti- PD1/PDL-1, will be assigned to arm 1 (durvalumab alone); at disease progression, they will be eligible to cross over to one of the chemotherapy arms (arm 2-7), provided they meet all the eligibility criteria, including adequate washout.

Patients with biliary cancers who have not received prior anti-PD1/PDL-1 will be enrolled on arm 1. Those having received prior anti-PD1/PDL-1 agents will preferentially be enrolled on arm 2, due to the potential benefit to gemcitabine in this histology. Prior treatment with gemcitabine will be allowed, and it is expected that the majority of patients with biliary cancer will have received prior gemcitabine-based therapy as part of standard of care.

For the proposed study, we will analyze biopsy samples from a total of 10 patients with refractory biliary cancers who have adequate biopsy samples at multiple timepoints. This will include 5 patients who receive durvalumab alone and 5 who receive durvalumab +gemcitabine.

References

1. Bezu, L., et al., Combinatorial strategies for the induction of immunogenic cell death. Front Immunol, 2015. 6: p. 187.

2. Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8.