CRS-HIPEC for Colorectal Cancer

Overseen By Ashley Shores

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Kansas Medical Center

Must not be taking: Investigational agents

Disqualifiers: Metastatic disease, Allergic reactions, 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: Unknown

Duration: Immediate and short-term surgical recovery up to 90 days post-hospital discharge

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how two drugs, mitomycin-C and melphalan (a chemotherapy drug), affect individuals with specific abdominal cancers, such as colorectal or high-grade appendiceal cancer. Researchers will compare the safety and side effects of these drugs when used during surgery. The trial suits those with colorectal or high-grade appendiceal cancer that has spread to the abdominal lining but not elsewhere, and who have not previously undergone this type of surgery. Participants must be prepared for a major abdominal operation and must not be receiving other cancer treatments simultaneously.

As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use other investigational agents or have had chemotherapy or radiotherapy within 4 weeks before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that melphalan is generally safe for treating cancer, but limited information exists about its use specifically for colorectal peritoneal carcinomatosis. In other studies, direct infusion of melphalan into the liver was mostly well-tolerated, with only a few serious side effects. However, melphalan carries risks due to its potency as a chemotherapy drug.

For mitomycin C, studies have demonstrated its common use in cancer treatment. It has been applied to various conditions and is generally well-tolerated by most patients. Some side effects have been reported, but these are usually manageable and not severe for most people.

Both treatments have been used effectively in cancer care in other situations. Consulting a healthcare provider is essential to understand what these treatments might mean for individual cases. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new approaches to tackling colorectal cancer, particularly for patients who may not respond well to standard chemotherapy options like FOLFOX or FOLFIRI. Melphalan is unique as it's administered directly into the abdominal cavity, allowing for high concentrations at the tumor site while minimizing systemic exposure. Mitomycin C, used here as a comparator, also follows this direct delivery method but with a maintenance dose, potentially enhancing its sustained effect on cancer cells. These innovative delivery methods aim to improve effectiveness and reduce side effects, which is why there's a lot of interest in these treatments.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that Melphalan, which participants in this trial may receive, can help treat colorectal cancer, particularly when the cancer has spread to the liver. One study found that about half of the patients who received Melphalan directly to the liver experienced a positive response, with the cancer either shrinking or ceasing to grow for some time.

For participants in this trial who receive Mitomycin C, studies suggest it can be effective for colorectal cancer that has spread to the lining of the abdomen. It is often used in heated chemotherapy treatments, applied directly to the cancerous area. Both treatments aim to target cancer cells but may work differently for each person. ^{1 2 3 6 7}

Who Is on the Research Team?

Mazin Al-kasspooles, MD

Principal Investigator

The University of Kansas - Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with colorectal cancer or high-grade appendiceal cancer that hasn't spread beyond the peritoneum. They must be medically fit for major surgery and chemotherapy, have good organ function, and agree to use contraception. Exclusions include other active cancers, recent chemo or radiotherapy, severe illnesses, pregnancy/nursing, or allergies to study drugs.

Inclusion Criteria

My condition is due to cancer in my appendix or colon that has spread to the lining of my abdomen.

Recorded ASA classification

I can take care of myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

Pregnancy or nursing

I am currently being treated for another cancer.

Current or anticipated use of other investigational agents

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) using either mitomycin-C or melphalan

Immediate and short-term surgical recovery up to 90 days post-hospital discharge

Follow-up

Participants are monitored for morbidity and mortality using the Comprehensive Complication Index (CCI) score every 3 months until Year 2

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Melphalan
• Mitomycin C

Trial Overview The trial compares two types of chemotherapy (mitomycin-C vs melphalan) used during a surgical procedure called CRS-HIPEC in patients with specific abdominal cancers. The focus is on assessing complications and side effects using various medical scores like CCI and CTCAE.

How Is the Trial Designed?

Group I: Melphalan Group Experimental Treatment 1 Intervention

Melphalan 60 mg/m2 (milligrams per meter squared) 45 minutes into the perfusion.

Group II: Mitomycin C Group Active Control 1 Intervention

Mitomycin-C initial dose of 15 mg/m2 (milligrams per meter squared) 45 minutes into the perfusion, a maintenance dose of 5 mg/m2 will be administered.

Melphalan is already approved in European Union, United States for the following indications:

Approved in European Union as Alkeran for:

• Multiple myeloma
• Malignant lymphoma
• Acute lymphoblastic leukemia
• Acute myeloblastic leukemia
• Childhood neuroblastoma
• Ovarian cancer
• Mammary adenocarcinoma

Approved in United States as Alkeran for:

• Multiple myeloma
• High-dose conditioning before hematopoietic stem cell transplant
• Uveal melanoma with unresectable hepatic metastases

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

Published Research Related to This Trial

In a systematic review of 11 studies involving 2091 patients, oxaliplatin (OX) used in hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) was associated with a significantly higher rate of major complications compared to mitomycin C (MMC).

Both OX and MMC showed similar survival outcomes for patients with peritoneal metastasis from colorectal cancer, suggesting that while OX may be effective, MMC could be the safer option for clinical use due to its lower complication rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxaliplatin versus mitomycin C in HIPEC for peritoneal metastasis from colorectal cancer: a systematic review and meta-analysis of comparative studies. Zhang, X., Wu, Q., Wei, M., et al.[2021]

In a study of 84 patients, higher doses of melphalan (≥ 70 mg/m²) significantly increased the risk of severe side effects, with a 23-fold increase in mucositis and a 12-fold increase in diarrhea compared to lower doses.

The severity of melphalan-induced side effects was primarily dependent on the dose administered, suggesting that therapeutic drug monitoring or genotyping for specific genetic polymorphisms may not effectively optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects. Kühne, A., Sezer, O., Heider, U., et al.[2013]

EVOMELA, a new formulation of melphalan that is free from propylene glycol, has been shown to be safe and effective for high-dose conditioning in autologous stem cell transplantation for multiple myeloma, with a 100% overall response rate in a study of 61 patients.

The study reported low incidences of severe side effects, such as grade 3 mucositis (10%) and stomatitis (5%), indicating that EVOMELA has an acceptable safety profile compared to traditional formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. Hari, P., Aljitawi, OS., Arce-Lara, C., et al.[2017]

In a study of 514 multiple myeloma patients, the propylene glycol-free formulation of melphalan (PGF-mel) showed similar efficacy to the conventional propylene glycol-based formulation (PG-mel) in terms of relapse rates after high-dose melphalan with autologous hematopoietic cell transplantation.

However, PGF-mel was associated with fewer severe adverse events like mucositis and febrile neutropenia, leading to a preference for PG-mel despite the potential benefits of PGF-mel, due to cost considerations and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Khan, AM., Yucebay, F., Zhao, Q., et al.[2023]

In a study of 25 patients undergoing CRS/HIPEC with intraperitoneal melphalan, 88% achieved complete cytoreduction, indicating high efficacy for treating aggressive peritoneal carcinomatosis.

The overall survival rates were promising, with 1-year survival at 89.4% after melphalan treatment, and no postoperative mortality was reported, although 23% experienced significant morbidity, primarily myelosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melphalan: a promising agent in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Sardi, A., Jimenez, W., Nieroda, C., et al.[2022]

In a study of 102 patients with colorectal cancer and peritoneal carcinomatosis, there was no significant difference in overall survival between those receiving hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) and those receiving oxaliplatin.

However, patients treated with oxaliplatin experienced significantly higher postoperative complications (66.2% vs 35.3%) and longer intensive care unit stays, suggesting that MMC may be a safer option for HIPEC in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of hyperthermic intraperitoneal chemotherapy regimens for treatment of peritoneal-metastasized colorectal cancer. Spiegelberg, J., Neeff, H., Holzner, P., et al.[2020]

In a study of 287 patients with peritoneal metastasized colorectal cancer treated with CytoReductive Surgery (CRS) and Hyperthermic IntraPEritoneal Chemotherapy (HIPEC), 46% experienced disease recurrence after a median disease-free interval of 11.4 months, with recurrences primarily being locoregional (43%).

For patients who underwent surgical treatment for recurrence with curative intent, median survival increased significantly from 12 months to 43 months compared to those receiving palliative care, highlighting the potential benefit of aggressive surgical intervention in selected cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of recurrence following complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Braam, HJ., van Oudheusden, TR., de Hingh, IH., et al.[2014]

In a study involving 34 patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), melphalan was found to be an acceptable agent, with no postoperative deaths and manageable morbidity rates (26% grade 3 and 17% grade 4 complications).

Pharmacologic analysis indicated that melphalan achieved a high concentration in the peritoneal fluid compared to plasma, suggesting effective delivery to tumor sites, but further research is needed to compare its efficacy against other HIPEC agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitoneal chemotherapy with melphalan: a summary of clinical and pharmacological data in 34 patients. Bijelic, L., Sugarbaker, PH., Stuart, OA.[2022]

Out of 476 colorectal peritoneal metastases patients referred for CRS-HIPEC, 48% (227 patients) were deemed ineligible, primarily due to extensive peritoneal metastases, which significantly impacted their survival outcomes.

Patients who received systemic therapy after being deemed ineligible had a median overall survival of 17 months, while those receiving best supportive care had a much lower median survival of 4 months, highlighting the importance of treatment options even for ineligible patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment and Survival Outcomes for Patients with Colorectal Peritoneal Metastases Deemed Ineligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Results of a Retrospective Study. Dietz, MV., Ziekman, MJ., van Kooten, JP., et al.[2023]

In a study of 100 patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for colorectal cancer (CRC) metastases, the median disease-free survival (DFS) was found to be 13 months, indicating a significant but limited duration of remission after treatment.

The presence of the BRAF mutation was identified as a strong predictor of earlier recurrence, with patients showing a median DFS of only 7 months compared to 16 months for those without the mutation, suggesting that careful patient selection is crucial for optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of molecular biomarkers in outcomes and patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases of colorectal origin. Solomon, D., Leigh, N., Bekhor, E., et al.[2021]

In a study of 48 patients with peritoneal carcinomatosis from colorectal cancer, those treated with mitomycin-C (MMC) during hyperthermic intraperitoneal chemotherapy (HIPEC) had a longer median progression-free survival (PFS) of 20 months compared to 10 months for those treated with melphalan.

The only significant predictor of survival was a peritoneal cancer index (PCI) of 20 or higher, highlighting the importance of tumor burden in determining patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Survival in Patients with Isolated Peritoneal Carcinomatosis from Colorectal Cancer Treated with Cytoreduction and Melphalan or Mitomycin-C as Hyperthermic Intraperitoneal Chemotherapy Agent. Sipok, A., Sardi, A., Nieroda, C., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06607458

Study Details | NCT06607458 | Evaluation of the Safety ... The goal of this clinical trial is to learn if using a liver-directed therapy with high dose chemotherapy followed by approved cancer treatment to treat ...

2. investors.delcath.com investors.delcath.com/news-releases/news-release-details/delcath-systems-announces-first-patient-dosed-phase-2-clinical

Delcath Systems Announces First Patient Dosed in Phase 2 ... Delcath Systems Announces First Patient Dosed in Phase 2 Clinical Trial of HEPZATO™ in Liver-Dominant Metastatic Colorectal Cancer. August 19, ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35025911/

Prospective evaluation of percutaneous hepatic perfusion ... Conclusion: M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10414734/

Isolated Hepatic Perfusion With Melphalan for Patients With ... About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0923753419416062

Isolated hepatic melphalan perfusion of colorectal liver ... This study reports the results of IHP with 200 mg melphalan in 105 colorectal cancer patients. Hepatic response rate was 50% with a median progression-free ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf

ALKERAN - accessdata.fda.gov WARNING. ALKERAN (melphalan) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.01705

Isolated Hepatic Perfusion With Melphalan for Patients ... Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking.