Peposertib + Avelumab + Radiation for Hepatobiliary Cancer
Recruiting in Palo Alto (17 mi)
+43 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Immune checkpoint inhibitors, PPIs
Disqualifiers: Uncontrolled CNS disease, Active autoimmune, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase I/II trial studies the best dose and side effects of peposertib and to see how well it works with avelumab and hypofractionated radiation therapy in treating patients with solid tumors and hepatobiliary malignancies that have spread to other places in the body (advanced/metastatic). Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving peposertib in combination with avelumab and hypofractionated radiation therapy may work better than other standard chemotherapy, hormonal, targeted, or immunotherapy medicines available in treating patients with solid tumors and hepatobiliary malignancies.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications before starting the study. Specifically, you must discontinue medications that are strong inhibitors or inducers of certain liver enzymes (CYP3A4/5 or CYP2C19) and proton-pump inhibitors (PPIs) before starting the trial drugs. It's important to discuss your current medications with the trial team to see if any need to be stopped.
What data supports the effectiveness of the treatment Peposertib + Avelumab + Radiation for Hepatobiliary Cancer?
A study on avelumab, one of the drugs in the treatment, showed it was effective in patients with advanced liver cancer who had previously been treated with another drug called sorafenib. Additionally, combining radiotherapy with immune therapies like avelumab has shown promise in other cancers, suggesting potential benefits for hepatobiliary cancer as well.
12345Is the combination of Peposertib, Avelumab, and Radiation generally safe for humans?
The available research on hypofractionated radiotherapy (a type of radiation treatment) combined with anti-PD-1 therapy (a type of immunotherapy) in melanoma patients did not report any unusual adverse events, suggesting it is generally safe. However, specific safety data for the combination of Peposertib, Avelumab, and Radiation in hepatobiliary cancer is not provided in the available studies.
13567What makes the treatment of Peposertib, Avelumab, and Radiation unique for hepatobiliary cancer?
This treatment is unique because it combines Peposertib, a drug that may enhance the effects of radiation, with Avelumab, an immune therapy that helps the body's immune system attack cancer cells, and hypofractionated radiation therapy, which delivers higher doses of radiation in fewer sessions. This combination aims to improve the effectiveness of treatment by using different methods to target cancer cells.
12389Eligibility Criteria
Adults with advanced/metastatic solid tumors or hepatobiliary malignancies, who have tried standard treatments without success or declined them. They must be in relatively good health (ECOG <=2), have measurable cancer lesions, and agree to biopsies if needed. Pregnant women, those with certain psychiatric illnesses, uncontrolled diseases, recent live vaccinations, or on strong immune system drugs can't join.Inclusion Criteria
I can swallow and keep down pills.
I can take care of myself but may not be able to do heavy physical work.
I have an advanced tumor that has not responded to or cannot be treated by standard therapies.
+25 more
Exclusion Criteria
I have not had a serious infection in the last 4 weeks.
I do not have any uncontrolled illnesses.
I have received immunotherapy before.
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Radiation
Patients undergo 8 fractions of hypofractionated radiation therapy every day on days -17 to -7
2 weeks
8 visits (in-person)
Treatment
Patients receive peposertib orally twice daily on days 1-28 and avelumab intravenously on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
28 days per cycle
2 visits (in-person) per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment completion
Up to 12 months
1 visit at 30 days, then every 3 months for 1 year, every 6 months for year 2, then annually
Participant Groups
The trial is testing Peposertib combined with Avelumab and hypofractionated radiation therapy against advanced cancers. It aims to find the best dose of Peposertib and see how well it works alongside an immunotherapy drug (Avelumab) and a type of intense short-term radiation treatment.
3Treatment groups
Experimental Treatment
Active Control
Group I: Phase I (hypofractionated RT, peposertib, avelumab)Experimental Treatment6 Interventions
Patients with advanced/metastatic malignant solid tumors undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, biopsy, and collection of blood samples during screening and on study.
Group II: Arm B (hypofractionated RT, peposertib, avelumab)Experimental Treatment5 Interventions
Patients undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive peposertib PO BID on days 1-28, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, CT, and collection of blood on the trial.
Group III: Arm A (hypofractionated RT, avelumab)Active Control5 Interventions
Patients undergo 8 fractions of hypofractionated RT QD on days -17 to -7. Patients also receive avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, CT, and collection of blood on the trial.
Avelumab is already approved in European Union, United States, Japan for the following indications:
🇪🇺 Approved in European Union as Bavencio for:
- Merkel cell carcinoma
- Renal cell carcinoma
- Urothelial carcinoma
🇺🇸 Approved in United States as Bavencio for:
- Merkel cell carcinoma
- Renal cell carcinoma
- Urothelial carcinoma
🇯🇵 Approved in Japan as Bavencio for:
- Merkel cell carcinoma
- Renal cell carcinoma
- Urothelial carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer CenterNew York, NY
NYP/Weill Cornell Medical CenterNew York, NY
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory CareIrvine, CA
UM Sylvester Comprehensive Cancer Center at AventuraAventura, FL
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients. [2021]Information on the role of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma patients is limited. We report on a prospective cohort of advanced melanoma patients treated simultaneously with radiotherapy and anti-PD-1 therapy between 01/01/15 and 30/06/16. Tumor evaluations (RECIST 1.1) were performed every 3 months on radiated and non-radiated lesions. Twenty-five advanced melanoma patients (64% AJCC stage IV M1c, 64% on second-line treatment or more, 60% with elevated LDH serum levels) were included. Radiotherapy was performed early (median: 24 days) after the first anti-PD-1 dose in 15 patients with rapidly progressing symptomatic lesion(s) or later (median: 5.4 months) in 10 patients with progressive disease (PD) despite PD-1 blockade. Radiotherapy was limited to one organ in 24 patients and consisted mainly of hypo-fractioned radiotherapy (median dose 26 Gy in 3-5 fractions, 17 patients) or brain radiosurgery (5 patients). Median follow-up after first anti-PD-1 dose was 16.9 m (range 2.7-27.4), with 44% of patients alive at last follow-up. For radiated lesions, rates of complete (CR), partial (PR) responses, stable disease (SD) or PD were 24%, 12%, 24%, and 32%, respectively. For non-radiated lesions, rates of CR, PR, SD, and PD were 20%, 19%, 12%, and 40%, respectively. Responses achieved after radiotherapy for radiated and non-radiated areas were correlated (Pearson correlation r: 0.89, P<0.0001) suggesting an abscopal effect. Five patients with CR remained disease-free after discontinuation of anti-PD-1 for a median of 9.5 months. No unusual adverse event was recorded. Hypo-fractionated radiotherapy may enhance efficacy of anti-PD1 therapy in difficult-to-treat patients. Controlled studies are needed.
Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. [2023]The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma.
Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). [2023]To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC).
Phase II Study of Avelumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib. [2022]This study investigated the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with advanced hepatocellular carcinoma previously treated with sorafenib (NCT03389126).
Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial. [2022]There are a lack of studies about whether radiation dose escalation synergizes with immunotherapy and targeted therapy in pancreatic cancer. In this study, we performed a secondary analysis to investigate whether a high radiation dose rather than a low dose plus pembrolizumab and trametinib provided improved survival compared with gemcitabine in post-operative locally recurrent pancreatic cancer.
Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy. [2021]Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3-5 sessions, 20-26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.
Phase 2 study of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy in patients with refractory pancreatic cancer (TRIPLE-R). [2023]Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC).
Nab-paclitaxel and gemcitabine plus camrelizumab and radiotherapy versus nab-paclitaxel and gemcitabine alone for locally advanced pancreatic adenocarcinoma: a prospective cohort study. [2023]Treatment options specifically for patients with locally advanced pancreatic adenocarcinoma (LAPC) are scare and chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments for LAPC, and both of them may synergize with chemotherapy. Therefore, in this prospective cohort study, we compared the efficacy and safety of nab-paclitaxel plus gemcitabine combined with anti-programmed cell death (PD-1) immunotherapy and radiotherapy (hereafter, combination treatment) versus nab-paclitaxel plus gemcitabine (chemotherapy alone) in the treatment of LAPC. In the combination group, participants received conventional fractionated radiotherapy with doses ranging from 54 to 63 Gy in 28 fractions, intravenous camrelizumab 200 mg once every 3 weeks, and intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death or unacceptable toxicity. In the chemotherapy group, participants received intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles. From April, 2020 to December, 2021, 96 participants with LAPC were prospectively enrolled with 32 received combination treatment and 64 received chemotherapy alone at a single center. The combination treatment yielded significantly longer median overall-survival (22.3 months vs. 18.6 months, P = 0.031) and progression-free survival (12.0 months vs. 10.5 months, P = 0.043) than chemotherapy alone did. And the incidence of severe adverse events was not significantly different between the combination group and chemotherapy group (P = 0.856). In conclusion, nab-paclitaxel plus gemcitabine combined with anti-PD-1 immunotherapy and radiotherapy was effective and safe for LAPC patients, and it warrants further investigation in larger randomized trials.
Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination. [2020]Label="PURPOSE">A driving factor in pancreatic ductal adenocarcinoma (PDAC) treatment resistance is the tumor microenvironment, which is highly immunosuppressive. One potent immunologic adjuvant is radiotherapy. Radiation, however, has also been shown to induce immunosuppressive factors, which can contribute to tumor progression and formation of fibrotic tumor stroma. To capitalize on the immunogenic effects of radiation and obtain a durable tumor response, radiation must be rationally combined with targeted therapies to mitigate the influx of immunosuppressive cells and fibrosis. One such target is ephrinB2, which is overexpressed in PDAC and correlates negatively with prognosis.Experimental Design: On the basis of previous studies of ephrinB2 ligand-EphB4 receptor signaling, we hypothesized that inhibition of ephrinB2-EphB4 combined with radiation can regulate the microenvironment response postradiation, leading to increased tumor control in PDAC. This hypothesis was explored using both cell lines and in vivo human and mouse tumor models.