Chemotherapy Dosing Strategies for Peritoneal Carcinomatosis

Recruiting at 1 trial location

Overseen By Prakash Pandalai, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Prakash Pandalai

Must not be taking: Investigational agents

Disqualifiers: Extra-abdominal metastases, Brain metastases, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

100 Participants Needed

Trial Summary

What is the purpose of this trial?

Peritoneal carcinomatosis from advanced gastro-intestinal malignancy has historically been associated with poor overall survival (≤ 12 months) with few treatment options. Cytoreductive surgery (CRS), which involves removal of all macroscopic tumor nodules, combined with direct administration of heated intra-peritoneal (IP) chemotherapy (HIPEC) to the affected peritoneal surfaces, has been shown to be an effective treatment option that extends overall survival among certain cases of peritoneal carcinomatosis. IP chemotherapy allows delivery of a high dose of cytostatic drug directly onto the peritoneal surfaces at risk for microscopic residual disease while systemic exposure remains limited. Additionally, hyperthermia is known to enhance the cytotoxicity of several agents (including Mitomycin C) and improves the depth of peritoneal penetration. This trial will be a randomized phase 2 comparison of flat dose versus weight-based dose Mitomycin C. The hypothesis of this study is that HIPEC weight-based dosing may result in similarly effective peritoneal Mitomycin C concentrations with less systemic absorption and potential systemic toxicity, compared with the HIPEC flat dosing approach in patients undergoing CRS/HIPEC.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot have had chemotherapy or radiotherapy within 4 weeks before joining the study. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Mitomycin C for treating peritoneal carcinomatosis?

Research shows that Mitomycin C, when used in a heated form directly in the abdomen, can reach high concentrations in the tumor area with limited side effects, making it a potentially effective treatment for peritoneal carcinomatosis. In a study, 8 out of 14 patients treated with this method remained alive without signs of disease after 10 months. ^{1 2 3 4 5}

Is Mitomycin C generally safe for humans?

Mitomycin C can cause kidney problems, especially at higher doses, and some patients may experience a drop in white blood cells, which can lead to infections. Safety concerns are often related to the dose and method of administration. ^{3 6 7 8 9}

How is the drug Mitomycin C used in treating peritoneal carcinomatosis unique?

Mitomycin C is unique in treating peritoneal carcinomatosis because it is administered directly into the abdominal cavity using a heated solution, which helps concentrate the drug at the tumor site while minimizing side effects throughout the body. ^{1 3 4 10 11}

Research Team

Prakash Pandalai, MD

Principal Investigator

University of Kentucky

Eligibility Criteria

This trial is for patients with specific abdominal cancers (like appendiceal cancer or colorectal cancer that has spread to the lining of the abdomen) who are fit enough for surgery and have a life expectancy over 3 months. They must understand and agree to the study's terms, have good organ function, and not be pregnant or breastfeeding. People with metastases outside the abdomen, recent chemotherapy or radiotherapy, ongoing severe illness, or allergies to similar drugs cannot join.

Inclusion Criteria

You are a suitable candidate for a surgery that aims to remove as much of the tumor as possible.

Patients diagnosed with one of the following: low-grade appendiceal mucinous neoplasm, appendiceal cancer with peritoneal carcinomatosis, colorectal cancer with peritoneal carcinomatosis

ECOG performance status < 3

Exclusion Criteria

Any extra-abdominal metastases

Untreated lung metastases

Liver metastases not amenable to resection or ablation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cytoreductive Surgery and HIPEC

Participants undergo cytoreductive surgery followed by intra-operative administration of heated intra-peritoneal chemotherapy (HIPEC) with either flat dose or weight-based dose of Mitomycin C

1 day

1 visit (in-person, surgical procedure)

Immediate Post-operative Monitoring

Participants are monitored for pharmacokinetics of Mitomycin C, including drug clearance, area under the curve, and half-life

Approximately 20 hours

Continuous monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Mitomycin C

Trial Overview The study is testing two ways of giving Mitomycin C during heated chemo after tumor-removing surgery: one based on patient weight (12.5 mg/m2) and another as a flat dose (40 mg). The goal is to see if weight-based dosing can effectively target peritoneal surfaces while reducing overall toxicity compared to flat dosing.

Participant Groups

Group I: Weight-Based Mitomycin C Experimental Treatment 1 Intervention

Participants in this group will receive weight-based dosing of mitomycin C intra-operatively: 1) 9 mg/m2 at minute 0 and 2) 3.5 mg/m2 at minute 60 for total dose of 12.5 mg/m2. Mitomycin C will be delivered via HIPEC (hyperthermic intraperitoneal chemotherapy).

Group II: Flat Dose Mitomycin C Experimental Treatment 1 Intervention

Participants in this group will receive flat doses of mitomycin C intra-operatively: 1) 30mg at minute 0 and 2) 10mg at minute 60. Mitomycin C will be delivered via HIPEC (hyperthermic intraperitoneal chemotherapy).

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

Approved in United States as Mitomycin C for:

• Stomach cancer
• Pancreatic cancer
• Peritoneal carcinomatosis (as part of HIPEC procedure)

Approved in European Union as Mitomycin C for:

• Stomach cancer
• Pancreatic cancer
• Peritoneal carcinomatosis (as part of HIPEC procedure)

Approved in Canada as Mitomycin C for:

• Stomach cancer
• Pancreatic cancer
• Peritoneal carcinomatosis (as part of HIPEC procedure)

Approved in Japan as Mitomycin C for:

• Stomach cancer
• Pancreatic cancer
• Peritoneal carcinomatosis (as part of HIPEC procedure)

Who Is Running the Clinical Trial?

Prakash Pandalai

Lead Sponsor

Trials

1

Recruited

100+

Findings from Research

In a study of 28 patients with peritoneal carcinomatosis, intraperitoneal chemohyperthermic perfusion (ICHP) of mitomycin C (MMC) resulted in high concentrations of the drug in the peritoneal cavity while maintaining limited systemic exposure, suggesting a targeted approach to treatment.

The pharmacokinetics of MMC showed a mean maximum plasma concentration of 0.14 microg/ml and a low percentage of the dose recovered unchanged in urine (7.21%), indicating that ICHP effectively delivers the drug to the tumor site with reduced toxicity compared to systemic administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of mitomycin C after resection of peritoneal carcinomatosis and intraperitoneal chemohyperthermic perfusion. Cerretani, D., Nencini, C., Urso, R., et al.[2013]

In a study of 15 patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy, the extent of peritoneal resection (total vs. less-extensive) did not significantly impact the pharmacokinetics of mitomycin C and doxorubicin, indicating that drug absorption into the bloodstream was similar regardless of the surgical approach.

The results suggest that the pharmacological barrier between the peritoneal cavity and plasma is not solely dependent on the integrity of the peritoneum, which could have implications for optimizing chemotherapy delivery in patients with peritoneal carcinomatosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics. de Lima Vazquez, V., Stuart, OA., Mohamed, F., et al.[2013]

In a study involving 14 athymic nude male rats, hyperthermic intraperitoneal chemotherapy (IPEC) using mitomycin C (MMC) showed high concentrations of the drug in the peritoneal and extraperitoneal tissues, indicating effective localized treatment.

The study found that increasing the temperature to 41°C during IPEC did not significantly alter the pharmacokinetics of MMC compared to normothermic conditions, suggesting that hyperthermia does not enhance the drug's absorption or effectiveness in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of hyperthermia on pharmacokinetics of intraperitoneal mitomycin C in rats investigated by microdialysis. Sørensen, O., Andersen, AM., Kristian, A., et al.[2014]

Intraperitoneal (IP) mitomycin C was administered to 14 patients with refractory peritoneal carcinomatosis (PC) from gynecologic cancers, showing minimal systemic toxicity and a manageable safety profile, although some experienced mild thrombocytopenia and abdominal pain due to chemical peritonitis.

Of the seven patients with measurable disease, six showed normalization of disease markers, and eight out of 14 patients remained alive without clinical evidence of disease after a median follow-up of 10 months, suggesting that IP mitomycin C could be an effective treatment option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraperitoneal mitomycin C in the treatment of peritoneal carcinomatosis following second-look surgery. Monk, BJ., Surwit, EA., Alberts, DS., et al.[2018]

Heated intraoperative intraperitoneal chemotherapy with mitomycin C (MMC) results in high concentrations of the drug in the peritoneal cavity while limiting systemic absorption, which suggests a targeted approach to treating peritoneal carcinomatosis.

Extensive peritoneal resections during surgery lead to increased systemic absorption of MMC, but the increase is minimal and unlikely to significantly raise the risk of systemic toxicity, indicating a favorable safety profile for this treatment method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies. Jacquet, P., Averbach, A., Stephens, AD., et al.[2022]

In a study of 142 patients with gastrointestinal cancer treated with mitomycin C, 8.5% experienced renal toxicity, indicating a significant risk associated with this chemotherapy drug.

The risk of renal toxicity was found to be dose-related, with only 1.6% of patients receiving less than 50 mg/m2 developing toxicity, compared to 10.8% for those receiving 50 to 69 mg/m2 and 27.8% for those receiving more than 70 mg/m2, suggesting that a safer total dose is below 50 mg/m2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renal complications of mitomycin C therapy with special reference to the total dose. Valavaara, R., Nordman, E.[2019]

In a study monitoring safety during hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with Mitomycin C (MMC), no detectable MMC was found in air samples or in the plasma of surgeons, indicating a low risk of exposure.

The use of double latex gloves effectively prevented dermal exposure to MMC, supporting their safety in surgical settings during HIPEC procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigations on safety of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with Mitomycin C. Schmid, K., Boettcher, MI., Pelz, JO., et al.[2013]

In a study of 45 patients undergoing cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer, neutropenia occurred in 40% of cases, indicating it is a common complication of this treatment.

The risk and severity of neutropenia were directly correlated with higher plasma concentrations of Mitomycin C (MMC) during HIPEC, suggesting that monitoring MMC levels, particularly at 30 minutes and 45 minutes after treatment, could help predict and manage neutropenia risk in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitomycin C Pharmacokinetics as Predictor of Severe Neutropenia in Hyperthermic Intraperitoneal Therapy. Kemmel, V., Mercoli, HA., Meyer, N., et al.[2022]

In a study of 314 patients undergoing heated intraperitoneal chemotherapy (HIPEC) with a fixed 40-mg dose of mitomycin C (MMC), the incidence of severe leukopenia and neutropenia was significantly lower than previously reported rates of 20-40% when dosing was based on weight or body surface area.

The findings suggest that routine prophylactic use of granulocyte-colony-stimulating factor (GCSF) is unnecessary for all patients, as only 7% developed severe leukopenia and 4.5% developed neutropenia, indicating that a fixed dose of MMC may reduce the risk of immunosuppression during HIPEC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conflicting Data on the Incidence of Leukopenia and Neutropenia After Heated Intraperitoneal Chemotherapy with Mitomycin C. Feferman, Y., Bhagwandin, S., Kim, J., et al.[2018]

In a study comparing HIPEC with Oxaliplatin (39 patients) and Mitomycin C (MMC, 56 patients) for colorectal cancer peritoneal carcinomatosis, Oxaliplatin patients had a higher extent of disease but less intra-operative blood loss compared to MMC patients.

Despite differences in toxicity, including neutropenia in MMC patients, there was no significant difference in recurrence-free survival (RFS) or overall survival (OS) between the two treatment groups, suggesting that neither agent showed a clear advantage in long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of Oxaliplatin or Mitomycin C in HIPEC treatment for peritoneal carcinomatosis from colorectal cancer: a comparative study. Hompes, D., D'Hoore, A., Wolthuis, A., et al.[2022]

Mitomycin-C (MMC) administered as a hyperthermic intraperitoneal lavage after surgery for advanced gastrointestinal cancer showed a significant absorption rate of about 70%, indicating effective drug delivery to the abdominal cavity.

The procedure had low morbidity primarily related to surgery, with mild to moderate myelosuppression as the main drug-related side effect, suggesting that this method of delivery is relatively safe and warrants further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically directed chemotherapy: heated intraperitoneal lavage with mitomycin C. Fernández-Trigo, V., Stuart, OA., Stephens, AD., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of mitomycin C after resection of peritoneal carcinomatosis and intraperitoneal chemohyperthermic perfusion. [2013]

2. Germany pubmed.ncbi.nlm.nih.gov

Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics. [2013]

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

Impact of hyperthermia on pharmacokinetics of intraperitoneal mitomycin C in rats investigated by microdialysis. [2014]

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

Intraperitoneal mitomycin C in the treatment of peritoneal carcinomatosis following second-look surgery. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies. [2022]

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

Renal complications of mitomycin C therapy with special reference to the total dose. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Investigations on safety of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with Mitomycin C. [2013]

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

Mitomycin C Pharmacokinetics as Predictor of Severe Neutropenia in Hyperthermic Intraperitoneal Therapy. [2022]

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

Conflicting Data on the Incidence of Leukopenia and Neutropenia After Heated Intraperitoneal Chemotherapy with Mitomycin C. [2018]

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

The use of Oxaliplatin or Mitomycin C in HIPEC treatment for peritoneal carcinomatosis from colorectal cancer: a comparative study. [2022]

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

Surgically directed chemotherapy: heated intraperitoneal lavage with mitomycin C. [2019]