Galunisertib + Chemotherapy for Rectal Cancer

Overseen By Larissa Lundgren

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Providence Health & Services

Must not be taking: Immunosuppressants, Chronic steroids, CYP3A4 drugs

Disqualifiers: Active infection, Autoimmune disease, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to see how effective and safe LY2157299, in combination with chemotherapy and radiation therapy, might be in treating rectal cancer. Also as part of this study, research will be done on tumor samples to see if it is possible to predict if patients will respond to treatment, and blood samples to look at the immune system response to study treatment. About 50 people will take part in this study. The study treatment will be given over an 8 week period and the investigators will continue to collect your health information for up to 5 years, as part of this study

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use strong CYP3A4 inhibitors and inducers while participating. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Galunisertib and chemotherapy for rectal cancer?

Research shows that capecitabine (Xeloda) combined with radiation therapy is effective in treating rectal cancer, achieving similar results to 5-FU plus radiation, which is a standard treatment. Capecitabine is designed to target tumors more effectively, leading to better outcomes and fewer side effects. ^{1 2 3 4 5}

Is the combination of Galunisertib and chemotherapy safe for humans?

Capecitabine (Xeloda), a drug similar to 5-fluorouracil (5-FU), has been used safely in various cancer treatments, including colorectal cancer, with manageable side effects. It is generally well-tolerated, with a lower incidence of severe side effects like neutropenia (low white blood cell count) compared to other chemotherapy drugs. However, there is a low but definite risk of heart-related side effects with 5-FU and capecitabine. ^{2 4 6 7 8}

What makes the Galunisertib + Chemotherapy treatment for rectal cancer unique?

This treatment combines Galunisertib, a novel drug that targets specific pathways in cancer cells, with standard chemotherapy and radiation, potentially enhancing the effectiveness of traditional treatments by making cancer cells more sensitive to radiation. ^{1 2 5 9 10}

Research Team

Todd Crocenzi, MD

Principal Investigator

Providence Health & Services

Kristina Young, MD, PhD

Principal Investigator

Providence Health & Services

Eligibility Criteria

Adults with confirmed rectal adenocarcinoma stages IIA-IIIC or stage IV suitable for tumor removal can join. They must be in good enough health to undergo treatment, not have serious heart conditions, active infections, autoimmune diseases, or a recent history of other cancers. Participants should not be pregnant and must use approved contraception.

Inclusion Criteria

My rectal cancer is confirmed and considered for surgery.

Ability to give informed consent and comply with the protocol

Laboratory values within specified ranges

Exclusion Criteria

Participation in any investigational drug study within 28 days of enrollment

Pregnant or lactating women

Abnormal Echocardiogram

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Initial Treatment with LY2157299

Participants receive a 14-day course of LY2157299 followed by a repeat biopsy and MRI

2 weeks

2 visits (in-person)

Chemoradiation

Participants undergo chemoradiation with Capecitabine or Fluorouracil, concurrent with another 14-day course of LY2157299

4-6 weeks

Daily visits for radiation (Monday through Friday)

Surgery

Tumor-specific mesorectal excision is performed 6-10 weeks after completing neoadjuvant therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for disease-free survival, progression-free survival, local recurrence, and overall survival

5 years

Every 3 months for 2 years, then every 6 months for years 3 and 4

Treatment Details

Interventions

• Capecitabine
• Fluorouracil
• LY2157299
• Radiation Therapy
• Tumor Specific Mesorectal Excision

Trial Overview The ExIST study is testing the safety and effectiveness of LY2157299 combined with chemotherapy (Fluorouracil or Capecitabine) and radiation therapy in treating rectal cancer over an 8-week period. The trial will also analyze tumor and blood samples to predict treatment response.

Participant Groups

Group I: LY2157299 + Chemoradiation + Surgery Experimental Treatment 4 Interventions

Patients will receive a 14 day course of LY2157299. On day 15 patients will begin chemoradiation treatment with Capecitabine or Fluorouracil. On day 29, patients will undergo another fourteen day course of LY2157299 concurrent with their ongoing chemoradiation treatment. Six to ten weeks after completing their neoadjuvant therapy, patient will undergo a tumor specific mesorectal excision as per standard of care.

Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

Providence Health & Services

Lead Sponsor

Trials

131

Recruited

827,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

Neoadjuvant chemoradiation, particularly with fluorouracil (5-FU) plus radiation, is now the preferred treatment for stage II/III rectal cancer, showing lower local relapse rates and better safety compared to postoperative treatments.

Capecitabine (Xeloda) plus radiation has been found to be as effective as 5-FU plus radiation, making it a viable alternative, while combinations with oxaliplatin or irinotecan show promise for improved outcomes and warrant further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation for rectal cancer: is more better? Patel, A., Puthillath, A., Yang, G., et al.[2018]

5-fluorouracil (5-FU) remains a key chemotherapy drug for colorectal cancer, but its oral form was previously abandoned due to inconsistent absorption; however, Xeloda (capecitabine) offers a solution by being an orally administered drug that is selectively activated in tumors, leading to higher local concentrations of 5-FU.

In phase II clinical trials for colorectal cancer, Xeloda demonstrated response rates of 21-24% and a median time to disease progression of 127-230 days, indicating its efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluoropyrimidines: a critical evaluation. Brito, RA., Medgyesy, D., Zukowski, TH., et al.[2017]

In a phase II study involving 54 patients with locally advanced rectal cancer, the combination of capecitabine and radiotherapy resulted in a pathologic complete response rate of 18% and a significant downstaging of tumors in 51% of patients, indicating its efficacy as a neoadjuvant treatment.

The treatment was well tolerated, with manageable side effects, and showed a sphincter preservation rate of 67% for tumors located close to the anal verge, making it a convenient alternative to traditional 5-FU infusion methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Krishnan, S., Janjan, NA., Skibber, JM., et al.[2022]

Xeloda (capecitabine) is an oral medication designed to convert into 5-fluorouracil (5-FU) specifically within tumors, potentially increasing anti-tumor activity while reducing systemic toxicity, as shown in various phase I and II trials.

In a phase II trial for colorectal cancer, Xeloda demonstrated a response rate of 21-24% across different regimens, with good tolerability and a longer time to disease progression for the intermittent regimen, which was selected for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential of Xeloda in colorectal cancer and other solid tumors. Cassidy, J.[2017]

The Phase I study determined that the maximal tolerated dose of capecitabine combined with standard radiotherapy for rectal cancer is 1600 mg/m²/day, which is important for future treatment protocols.

Dose-limiting toxicities were observed at lower doses, including Grade 3 diarrhea and skin toxicity, indicating that while capecitabine can be effective, careful monitoring for side effects is necessary during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer. Souglakos, J., Androulakis, N., Mavroudis, D., et al.[2019]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

In a study of 644 patients undergoing chemotherapy with 5-Fluorouracil (5FU) and oral capecitabine, 4.03% experienced cardiac-related symptoms, with a higher incidence (6.7%) observed in those receiving continuous 5FU infusion compared to other administration methods.

The study highlights that 5FU has a significant cardiotoxic effect that is schedule-dependent, while oral capecitabine also poses a low risk of cardiac events, indicating the need for careful monitoring during treatment with these drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. Kosmas, C., Kallistratos, MS., Kopterides, P., et al.[2022]

In a study of 452 patients with locally advanced rectal cancer, the rate of pathological complete response (pCR) was lower in those treated with oral capecitabine (9.5%) compared to intravenous 5-fluorouracil (20%), although this difference was not statistically significant (P = 0.082).

Despite the lower pCR rate with capecitabine, achieving pCR was found to be a strong independent predictor of survival, highlighting the importance of effective neoadjuvant chemotherapy in improving clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing pathological complete response rate using oral capecitabine versus infusional 5-fluorouracil with preoperative radiotherapy in rectal cancer treatment. Jootun, N., Evans, T., Mak, J., et al.[2018]

Combining capecitabine (an oral fluoropyrimidine) with radiation therapy shows promise as a more convenient and effective approach for treating gastrointestinal cancers, with ongoing studies examining its efficacy compared to infusional fluorouracil (5-FU).

Capecitabine's activation to 5-FU is enhanced by thymidine phosphorylase, which is more active in tumor tissues, potentially leading to better drug accumulation in tumors and improved outcomes in radiation therapy, as indicated by ongoing and planned clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine and radiation therapy for advanced gastrointestinal malignancies. Rich, T.[2015]

References

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

Neoadjuvant chemoradiation for rectal cancer: is more better? [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Fluoropyrimidines: a critical evaluation. [2017]

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

Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Potential of Xeloda in colorectal cancer and other solid tumors. [2017]

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

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer. [2019]

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

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. [2022]

8. Australia pubmed.ncbi.nlm.nih.gov

Comparing pathological complete response rate using oral capecitabine versus infusional 5-fluorouracil with preoperative radiotherapy in rectal cancer treatment. [2018]

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

Capecitabine and radiation therapy for advanced gastrointestinal malignancies. [2015]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Current status of intensified neo-adjuvant systemic therapy in locally advanced rectal cancer. [2021]