Peposertib + Radiation Therapy for Pancreatic Cancer

Recruiting at 40 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP inhibitors, CYP inducers, PPIs

Disqualifiers: Metastatic disease, Abdominal radiation, others

Compensation: Varies

Number of Visits: 41

98 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the safety, side effects and best dose of M3814 and to see how well it works when given together with radiation therapy in treating patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced). M3814 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 M3814 and hypofractionated radiation therapy together may be safe, tolerable and/or more effective than radiation therapy alone in treating patients with locally advanced pancreatic cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically those that are strong inducers or inhibitors of certain liver enzymes (CYP3A4/5, CYP2C9, and CYP2C19) and some other specific drugs. You should discuss with the study doctor to see if alternative medications can be used. Proton-pump inhibitors must also be stopped at least 5 days before starting the trial.

What data supports the effectiveness of the treatment Peposertib + Radiation Therapy for Pancreatic Cancer?

Research shows that hypofractionated radiotherapy, which is part of this treatment, can be safely combined with chemotherapy like gemcitabine for pancreatic cancer, potentially improving treatment timing and outcomes. ^{1 2 3 4 5}

Is the combination of Peposertib and hypofractionated radiation therapy safe for humans?

Studies on hypofractionated radiotherapy (a type of radiation treatment given in larger doses over fewer sessions) for pancreatic cancer suggest that it is generally safe, but the tolerance of nearby normal tissues is a concern. Safety data specific to Peposertib combined with this type of radiation therapy is not detailed in the provided studies. ^{3 4 6 7 8}

What makes the Peposertib + Radiation Therapy treatment unique for pancreatic cancer?

This treatment combines Peposertib, a drug that may enhance the effects of radiation, with hypofractionated radiation therapy, which delivers higher doses of radiation over a shorter period. This approach aims to improve treatment effectiveness and allow for earlier administration of chemotherapy compared to traditional methods. ^{2 3 5 7 9}

Research Team

Sarah L Davis

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Eligibility Criteria

Adults with localized pancreatic cancer that's inoperable but hasn't spread, who've completed 4-6 months of specific chemotherapy. They must be generally healthy, HIV or hepatitis B/C positive patients can join if their viral load is undetectable. Women of childbearing age need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

Received 4-6 months of induction chemotherapy with either fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX) or gemcitabine/Abraxane, as per standard of care

Patients must have locally advanced pancreatic cancer according to National Comprehensive Cancer Network (NCCN) Guidelines (version 1.2020) on CT scan performed within 21 days of registration

Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1

Exclusion Criteria

Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2CP, and CYP2C19. Concomitant use of CYP1A2, CYP2B6, and CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:

Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy grade =< 2

History of allergic reactions attributed to compounds of similar chemical or biologic composition to M3814 (peposertib)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase I Treatment

Patients undergo hypofractionated radiation therapy for 5 fractions every other day over 2 weeks and receive M3814 orally once daily for 14 days

2 weeks

5 visits (in-person)

Phase II Treatment

Patients are randomized to receive either hypofractionated radiation therapy with M3814 or placebo for 5 fractions every other day over 2 weeks

2 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Visits at 30, 60, and 90 days, then every 3 months

Treatment Details

Interventions

• Hypofractionated Radiation Therapy
• M3814 (Peposertib)

Trial Overview The trial tests M3814 (Peposertib) combined with hypofractionated radiation therapy versus radiation alone. The goal is to find the safest dose of M3814 and see if it's more effective when paired with this intense, short-term radiation treatment for pancreatic cancer.

Participant Groups

Group I: Phase II Group I (hypofractionated radiation therapy M3814) Experimental Treatment 6 Interventions

Patients in Phase II undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity.Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Group II: Phase I (hypofractionated radiation therapy, M3814) Experimental Treatment 6 Interventions

Patients in Phase I undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity.Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Group III: Phase II Group II(hypofractionated radiation therapy, placebo) Placebo Group 6 Interventions

Patients in Phase II undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive placebo PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Hypofractionated Radiation Therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Approved in European Union as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Approved in Canada as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 170 patients with unresectable non-metastatic pancreatic cancer, hypofractionated radiotherapy combined with full-dose gemcitabine resulted in significantly better overall survival (52% at 1 year) and distant metastasis-free survival (41% at 1 year) compared to standard fractionation radiotherapy with 5-fluorouracil (36% and 24%, respectively).

Both treatment regimens showed similar rates of gastrointestinal toxicities, indicating that the hypofractionated RT with gemcitabine is not only more effective but also has a comparable safety profile to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: a Multi-Institution Experience. Rakhra, S., Strauss, JB., Robertson, J., et al.[2023]

In a study of 16 patients with locally advanced pancreatic cancer, the combination of a single 25 Gy stereotactic body radiotherapy (SBRT) session with gemcitabine chemotherapy resulted in a median survival of 11.4 months, comparable to conventional treatments.

While the treatment showed good local control, there was a notable incidence of late gastrointestinal toxicity, including duodenal ulcers, highlighting the need for careful monitoring of patients post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Schellenberg, D., Goodman, KA., Lee, F., et al.[2022]

In a study involving 9 patients with locally advanced pancreatic cancer, hypofractionated radiotherapy at 45 Gy in 15 fractions was well-tolerated, with no dose-limiting toxicities observed, allowing for timely initiation of full-dose gemcitabine chemotherapy.

However, the lower dose of 40 Gy in 8 fractions resulted in significant side effects, preventing timely chemotherapy initiation in most patients, indicating that this regimen is not feasible for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of hypofractionated radiotherapy followed by systemic chemotherapy with full-dose gemcitabine in patients with unresectable locally advanced pancreatic cancer. Furuse, J., Ishii, H., Kawashima, M., et al.[2022]

In a pilot study involving 10 patients with unresectable pancreatic adenocarcinoma, hypofractionated intensity modulated radiotherapy (H-IMRT) demonstrated a high local control rate, with tumor response observed in 9 out of 10 patients.

The treatment was associated with manageable gastrointestinal toxicity, which correlated with the dose received by the duodenum, and resulted in promising 1-year overall and disease-free survival rates of 83.3% and 68.6%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated intensity-modulated radiotherapy in locally advanced unresectable pancreatic cancer: A pilot study. De Felice, F., Benevento, I., Bulzonetti, N., et al.[2020]

The hyperfractionated accelerated radiotherapy (HART) combined with gemcitabine showed a median survival of 12.9 months for patients with unresectable pancreatic cancer, which is slightly better than the 11.3 months observed with standard-fractionated radiotherapy (SFRT).

HART required significantly fewer treatment days (35.5 days) compared to SFRT (41.3 days) while maintaining similar toxicity profiles and response rates, indicating it is a more efficient treatment option without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of hyper-fractionated accelerated and standard fractionated radiotherapy with concomitant low-dose gemcitabine for unresectable pancreatic cancer. Maemura, K., Shinchi, H., Noma, H., et al.[2022]

In a study of 75 patients with 108 brain metastases treated with hypofractionated stereotactic radiotherapy (hfSRT), a cumulative biological equivalent dose (EQD2) of ≥35 Gy was found to be the most effective for achieving better local control of tumors, with a median local control time of 14.9 months compared to 3.4 months for doses ≤35 Gy.

While higher doses (EQD2 >35 Gy) were associated with increased rates of mild toxicity (31% vs. 8.3% for ≤35 Gy), the treatment was still considered safe, indicating that hfSRT can effectively manage limited brain metastases with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic radiotherapy of limited brain metastases: a single-centre individualized treatment approach. Märtens, B., Janssen, S., Werner, M., et al.[2022]

In a study of 61 patients with locally advanced pancreatic adenocarcinoma, hypofractionated radiotherapy resulted in a 33% incidence of acute gastrointestinal grade 2 toxicity, highlighting the need to manage side effects during treatment.

Dosimetric analysis revealed that higher doses to the stomach (V20[%]) and duodenum (V40[%] and V45[%]) were significant predictors of both acute and late anatomical toxicity, suggesting that careful planning of radiation doses can help minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. Cattaneo, GM., Passoni, P., Longobardi, B., et al.[2023]

In a study of 294 patients receiving hypofractionated stereotactic radiotherapy (HFSRT) for brain metastases, the 12-month rate of radiation necrosis (RN) was found to be 8.8%, indicating a relatively low risk overall.

The risk of RN was significantly higher for patients treated with higher dose regimens (27 Gy in 3 fractions and 35 Gy in 5 fractions) compared to a moderate dose regimen (30 Gy in 5 fractions), and also increased in patients who had received immunotherapy within 3 months prior to HFSRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of radiation necrosis after hypofractionated stereotactic radiotherapy (HFSRT) for brain metastases: a single center retrospective study. Di Perri, D., Tanguy, R., Malet, C., et al.[2021]

In a study of 28 patients with pancreatic cancer who received hypofractionated stereotactic body radiation therapy (SBRT) after prior radiation, 85.7% were free from local progression, indicating that SBRT can effectively control local disease.

The treatment was generally well-tolerated, with only mild to moderate side effects reported, but the overall survival rate remained low, with a median survival of 5.9 months, highlighting the challenges in treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for reirradiation of localized adenocarcinoma of the pancreas. Lominska, CE., Unger, K., Nasr, NM., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: a Multi-Institution Experience. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. [2022]

3. Greece pubmed.ncbi.nlm.nih.gov

A phase I study of hypofractionated radiotherapy followed by systemic chemotherapy with full-dose gemcitabine in patients with unresectable locally advanced pancreatic cancer. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Hypofractionated intensity-modulated radiotherapy in locally advanced unresectable pancreatic cancer: A pilot study. [2020]

5. Greece pubmed.ncbi.nlm.nih.gov

Comparison of hyper-fractionated accelerated and standard fractionated radiotherapy with concomitant low-dose gemcitabine for unresectable pancreatic cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic radiotherapy of limited brain metastases: a single-centre individualized treatment approach. [2022]

7. Ireland pubmed.ncbi.nlm.nih.gov

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Risk of radiation necrosis after hypofractionated stereotactic radiotherapy (HFSRT) for brain metastases: a single center retrospective study. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for reirradiation of localized adenocarcinoma of the pancreas. [2022]