A-dmDT390-bisFv(UCHT1) Fusion Protein With Ionizing Radiation and Pembrolizumab for the Treatment of Stage IV Melanoma
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|ClinicalTrials.gov Identifier: NCT02990416|
Recruitment Status : Unknown
Verified December 2016 by Angimmune LLC.
Recruitment status was: Not yet recruiting
First Posted : December 13, 2016
Last Update Posted : December 13, 2016
|Condition or disease||Intervention/treatment||Phase|
|Stage IV Melanoma||Biological: A-dmDT390-bisFv(UCHT1) Biological: Pembrolizumab Radiation: Ionizing Radiation||Phase 1 Phase 2|
The purpose of this trial is to test the hypothesis that A-dmDT390-bisFv(UCHT1) can act as an immunomodulator of late stage metastatic melanoma when combined with palliative radiation (to induce the priming of activated T cells with tumor antigens) and Pembrolizumab.
A-dmDT390-bisFv(UCHT1), an anti-T cell immunotoxin is currently being studied as a treatment for cutaneous T cell lymphoma and other CD3+ malignant diseases (NCT00611208 and NCT02943642). During the course of this study, data accumulated that A-dmDT390-bisFv(UCHT1) could be acting as an immunomodulator. This was based on the observation that four out of six partial responses converted to complete responses at times ranging between 6 and 24 months following the completion of the 4-day treatment protocol (serum half life ~45 min.) and no other treatment took place. Complete response durations were 4-6+ years.
Checkpoint inhibitors have revolutionized the treatment of certain solid tumors, notably melanoma, NSCLC and renal cancer. Yet the overall response rate remains low and the mechanisms limiting responses have not been elucidated.
Based on the findings that checkpoint inhibitors have higher response rates when the tumor neoantigen burden is higher (over 1 mutation per megabase, Shumacher & Schreiber, 2015) the investigators propose to increase the neoantigen burden by combining two distinct manipulations:
- Treatment with an anti-CD3 fusion protein Resimmune days 1-4 to induce a 20-fold increase in CD8+ central memory T cells and
- Treatment with anti-PD1 day 16 and q. 3 weeks to block PD-1/PD-L1 negative regulation on the newly activated T cells (Blake et al., 2015) and to block high levels of PD-1 in the tumor microenvironment (Ahmadzadeh et al., 2009).
Palliative tumor radiation day 5 will provide the tumor antigen release needed to convert the expanded central memory T cells to effector memory T cells.
The study will be a single-arm, uncontrolled phase I/II trial to estimate the safely of the combined treatment and then estimate the efficacy in terms of RECIST 1.1 in patients with stage Stage IV metastatic melanoma. The primary endpoint is the clinical response as defined by progression-free survival (PFS). The second end point will be tolerability to treatment. Secondary end points to be considered are overall survival (OS).
The study is conducted in 2 phases. In phase I (safety), the investigators will enroll 6 patients. In first stage, 25 total patients will be enrolled. Using Simon's two stage minimax design for phase II trials, the investigators plan to enroll a maximum of 63 patients.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||63 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Trial of the A-dmDT390-bisFv(UCHT1) Fusion Protein in Combination With Ionizing Radiation and Pembrolizumab for the Treatment of Stage IV Melanoma|
|Study Start Date :||January 2017|
|Estimated Primary Completion Date :||February 2018|
|Estimated Study Completion Date :||June 2018|
A-dmDT390-bisFv(UCHT1): 2.5 µg/kg 2x x 4 days, Ionizing Radiation: single treatment on day five of 14-24 Gy to a tumor, Pembrolizumab: 2 mg/kg IV every 3 weeks
anti-T cell immunotoxin (antibody targeting CD3 on T-cells tagged with diphtheria toxin without binding domain)
Other Name: Resimmune® (proposed marketing designation)
A humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1) with potential immune checkpoint inhibitory and antineoplastic activities.
Other Name: KEYTRUDA
Radiation: Ionizing Radiation
Electromagnetic or corpuscular radiation capable of producing ions, directly or indirectly, in its passage through matter.
- Clinical Response primary outcome measure is the change in Progression Free Survival time (PFS). [ Time Frame: 2 months, then at least every 3 months post treatment or until disease progression (maximum 36 months) ]The PFS time will be determined as the time from enrollment until the first adverse event (i.e., disease progression or death due to any cause).
- Changes in Clinical Response Rates [ Time Frame: 2 months, then at least every 3 months post treatment or until disease progression (maximum 36 months) ]Changes in clinical response rates (complete, partial, and sustained) along with 95% estimated confidence intervals compared to the historical record of Pembrolizumab and local palliative radiation. Disease progression and efficacy response will be determined using RECIST 1.1. At a minimum, CT scans of the chest, abdomen, and pelvis will be performed at study entry, at 2 months, and, if a response or stable disease, at least every 3 months (±7 days) for up to 1 year after the last dose of study drug, and/or at any time there is clinical evidence of disease progression, to evaluate disease status (assessed up to 36 months).
- Tolerability to Treatment [ Time Frame: 2 months, then at least every 3 months post treatment or until disease progression (maximum 36 months) ]Determine the tolerability of A-dmDT390-bisFv(UCHT1) at a total dose of 20 μg/kg when combined with Pembrolizumab and local palliative radiation towards metastatic lesions in stage IV melanoma as a percentage of patients experiencing serious adverse events. The cumulative number of CTCAE grade 3 or 4 toxic events either from lab data or clinical findings will be monitored. Multiple measurements will be aggregated to arrive at one reported value (e.g., Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment).
- Overall Survival, OS [ Time Frame: 2 months, then at least every 3 months post treatment (maximum 36 months) ]The OS time will be determined as the time from enrollment until death or last follow-up evaluation, assessed up to 36 months.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02990416
|Contact: Brown Cancer Center Clinical Trials Officefirstname.lastname@example.org|
|United States, Kentucky|
|James Graham Brown Cancer Center|
|Louisville, Kentucky, United States, 40202|
|Principal Investigator:||Jason Chesney, MD, PhD||James Graham Brown Cancer|