UCDCC#272: IL-2, Radiotherapy, and Pembrolizumab in Patients Refractory to Checkpoint Blockade

Non Small Cell Lung Cancer Clinical Trial

Official title: UCDCC#272: A Phase I/II Study of Intralesional IL-2, Hypofractionated Radiotherapy, and Pembrolizumab in Patients Refractory to Standard-of-Care PD-1/PD-L1 Checkpoint Blockade

Status Recruiting

Clinical Trial Summary

This is a phase I/II study that will evaluate the safety and toxicity of this combinatorial approach. Eligible patients >18 years of age with histologically proven metastatic NSCLC, melanoma, RCC, or HNSCC who have failed PD-1 / PD-L1 checkpoint blockade therapy will be enrolled. Patients must have a candidate treatment lesion (subcutaneous, nodal, or visceral) accessible and safe for radiotherapy and serial intralesional injections as specified by the protocol. They must also have at least one target lesion (distinct from treatment lesion and outside of treatment lesion radiation field) evaluable for response by RECIST.

This study will consist of a phase I dose escalation using a standard 3+3 design to determine safety and MTD of intralesional IL-2 which will be dose escalated in conjunction with standard fixed doses of RT and Pembrolizumab. At the MTD there will be a phase II dose expansion which will incorporate a simon-two stage design to assess efficacy and safety.

Patients will receive pembrolizumab and intralesional IL-2 in combination with hypofractionated radiotherapy.

Clinical Trial Description

This is a phase I/II study that will evaluate the safety and toxicity of this combinatorial approach. Eligible patients >18 years of age with histologically proven metastatic NSCLC, melanoma, RCC, or HNSCC who have failed PD-1 / PD-L1 checkpoint blockade therapy will be enrolled. Patients must have a candidate treatment lesion (subcutaneous, nodal, or visceral) accessible and safe for radiotherapy and serial intralesional injections as specified by the protocol. They must also have at least one target lesion (distinct from treatment lesion and outside of treatment lesion radiation field) evaluable for response by RECIST.

This study will consist of a phase I dose escalation using a standard 3+3 design to determine safety and MTD of intralesional IL-2 which will be dose escalated in conjunction with standard fixed doses of RT and Pembrolizumab. At the MTD there will be a phase II dose expansion which will incorporate a simon-two stage design to assess efficacy and safety.

Patients will receive pembrolizumab and intralesional IL-2 in combination with hypofractionated radiotherapy.

• Radiotherapy will be delivered to the treatment lesion during the second cycle of therapy using an 8 Gy x 3 fractions palliative regimen. Fractions may be delivered on consecutive or every other day but must be completed during week 1-2 of cycle 2 and will not be repeated in future cycles.

• Pembrolizumab will be delivered at 200 mg in three week cycles per standard protocol.

• A total of four interleukin-2 treatments will be delivered into the treatment lesion by intralesional injection biweekly (at least 48 hours apart) starting 24-96 hours after the completion of radiotherapy and to be completed during the second on-trial cycle of Pembrolizumab. Intralesional injections will be performed by direct visualization and/or palpation of the lesion or under ultrasound or CT guidance as indicated.

Patients will be assessed by a physician once during the first week of radiotherapy, during each intralesional IL-2 injection, and with every cycle of pembrolizumab during the first three cycles. Thereafter patients will be assessed every 30 days during the study period and will continue until disease progression. All patients on active treatment will be discussed at weekly conferences of the trial investigators. Routine laboratory evaluation will occur pre-treatment and every 30 days. For response assessment patient will have imaging pre-treatment and after every three cycles of Pembrolizumab. For collateral studies patients will undergo mandatory treatment lesion biopsies and blood draws pre-treatment and during the needle placement for the final IL-2 treatment.

Preliminary efficacy as determined by abscopal response rate, ORR, DCR and PFS will be assessed every 3 cycles. The patient will remain on protocol treatment until progression as determined by irRECIST, treatment is no longer tolerated, or the patient has completed 12 months of treatment. Patients on active treatment at 12 months may continue to receive pembrolizumab but will revert to standard of care (SOC) management and be labeled in "follow up". At this time only PFS and long-term toxicity data will be collected every 3 months.

The primary endpoint is to determine if this regimen converts patients with resistance to PD 1/PD-L1 checkpoint blockade into responders as determined by abscopal response rate (defined as response rate at lesions not treated with RT + IL-2) using irRECIST as well as ORR, DCR, and PFS using RECIST 1.1. The secondary endpoint is tolerability, safety, and toxicity using CTCAE v4.03. Correlative studies include immunophenotyping serial tumor biopsies and blood samples. ;

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Head and Neck Squamous Cell Carcinoma
• Metastatic Melanoma
• Metastatic Renal Cell Carcinoma
• Non Small Cell Lung Cancer
• Squamous Cell Carcinoma of Head and Neck

• NCT number: NCT03474497
• Study type: Interventional
• Source: University of California, Davis
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 20, 2019
• Completion date: December 2023