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

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this trial is to compare the morbidity and mortality of CRS-HIPEC using mitomycin-C versus melphalan for colorectal peritoneal carcinomatosis. Morbidity and mortality will measured using the Comprehensive Complication Index (CCI) score, Common terminology criteria for adverse events (CTCAE version 4.03), and the Clavien-Dindo Classification.

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.

What data supports the effectiveness of the drug Melphalan in the CRS-HIPEC treatment for colorectal cancer?

Research suggests that Melphalan, when used in hyperthermic intraperitoneal chemotherapy (HIPEC), may improve survival in patients with peritoneal carcinomatosis from colorectal cancer, especially in cases where other treatments have failed. Additionally, Melphalan has shown effectiveness in other cancers, indicating its potential as a promising agent in this context. ^{1 2 3 4 5}

Is CRS-HIPEC with melphalan safe for humans?

Melphalan, used in CRS-HIPEC, has been shown to have an acceptable safety profile in humans, with some patients experiencing severe side effects like mucositis (painful inflammation and ulceration of the mucous membranes), diarrhea, and myelosuppression (decreased bone marrow activity). However, studies indicate that the morbidity (complications) associated with its use in HIPEC is considered acceptable, with no reported deaths in the studies reviewed. ^{2 3 4 5 6}

How is the CRS-HIPEC treatment for colorectal cancer unique?

CRS-HIPEC for colorectal cancer is unique because it combines surgery to remove visible tumors with heated chemotherapy directly applied inside the abdomen, using drugs like Melphalan and Mitomycin C, which may offer targeted treatment for cancer spread in the abdominal area. ^{7 8 9 10 11}

Research Team

Mazin Al-kasspooles, MD

Principal Investigator

The University of Kansas - Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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 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 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]

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 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]

References

1. United States 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. [2022]

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

Melphalan: a promising agent in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. [2022]

3. Egypt pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitoneal chemotherapy with melphalan: a summary of clinical and pharmacological data in 34 patients. [2022]

4. United States 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. [2017]

5. United States 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. [2023]

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

Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects. [2013]

7. Germany 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. [2021]

8. Scotland 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. [2021]

9. China pubmed.ncbi.nlm.nih.gov

Comparison of hyperthermic intraperitoneal chemotherapy regimens for treatment of peritoneal-metastasized colorectal cancer. [2020]

10. United States 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. [2023]

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

Patterns of recurrence following complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. [2014]