HIPEC for Peritoneal Cancer

Overseen By Stephanie N Canady, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticancer therapy

Disqualifiers: Extra-abdominal metastases, Major surgery, others

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

Compensation: Varies

Number of Visits: 3

Duration: 7-21 days hospitalization post-surgery

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to improve treatment for peritoneal carcinomatosis, a cancer that spreads to the lining of the abdomen. After tumor-removing surgery, researchers test different chemotherapy drugs in a heated wash to determine the most effective combination. Participants will receive either cisplatin, doxorubicin, mitomycin C, or oxaliplatin during treatment. Suitable candidates for this trial have peritoneal carcinomatosis that surgery alone cannot fully remove. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have received intraperitoneal chemotherapy or other anti-cancer therapy within the last 4 weeks, you may not be eligible to participate.

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

Previous studies have shown that HIPEC (heated chemotherapy) with cisplatin and mitomycin C is generally well-tolerated. Some patients experienced manageable side effects like nausea or abdominal pain. Another study on the combination of cisplatin and doxorubicin with HIPEC showed similar results, with most side effects being mild to moderate, such as temporary changes in kidney function.

When HIPEC was used with oxaliplatin and 5-fluorouracil, research indicated it was also generally safe. Some patients experienced side effects like low blood cell counts and fatigue, but these were managed with supportive care.

For HIPEC with mitomycin C, studies showed it did not cause significant additional side effects beyond those expected from HIPEC. Side effects, when they occurred, were usually mild, such as temporary changes in blood counts or nausea.

Overall, these treatments have demonstrated a reasonable safety profile in studies conducted so far, with mostly manageable side effects. However, it is important to note that these studies are in early stages, and ongoing trials will provide more detailed safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine chemotherapy drugs like cisplatin, doxorubicin, mitomycin C, and oxaliplatin with a unique heated intraperitoneal chemotherapy (HIPEC) approach. Unlike traditional chemotherapy, which is usually delivered through the bloodstream, HIPEC administers heated chemotherapy directly into the abdominal cavity. This method allows for higher concentrations of drugs to target cancer cells in the peritoneal area while minimizing systemic side effects. The heat enhances the effectiveness of the drugs, potentially improving outcomes for patients with peritoneal cancer. This innovative approach could offer new hope where standard treatments like systemic chemotherapy might fall short.

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

Research has shown that HIPEC, a treatment involving heated chemotherapy after tumor-removal surgery, can improve survival rates for people with abdominal cancers. In this trial, participants will be randomly assigned to different treatment arms. One arm uses HIPEC with cisplatin and mitomycin C, which studies have found can increase the chance of surviving for five years to 83.3% in some cases. Another arm combines cisplatin and doxorubicin, linked to a significant decrease in death rates compared to standard chemotherapy. A separate arm uses oxaliplatin with 5-fluorouracil (5-FU), which has shown better control over tumor spread in the abdomen. Lastly, an arm with mitomycin C has extended survival times and led to better outcomes. Overall, these chemotherapy treatments have shown promise in improving survival and controlling cancer spread in the abdomen. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrew M Blakely, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with peritoneal carcinomatosis from ovarian, colorectal, appendiceal, or mesothelioma cancers that can't be fully removed by surgery. They must have good physical function and organ health, not received certain treatments recently, agree to use contraception and co-enroll in a tissue collection study.

Inclusion Criteria

Ability and willingness to co-enroll on the tissue collection protocol 13C0176, Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors.

Because therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 180 days after last study treatment; should a woman suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

My cancer, originating from the appendix, colon, ovary, or peritoneum, has spread within the abdomen.

Exclusion Criteria

I am HIV-positive with an undetectable viral load and on antiretroviral therapy.

I haven't had cancer treatment in the last 4 weeks.

I am allergic to medications that contain platinum.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for medical history, physical exam, imaging, and biopsy

Treatment

Participants undergo cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) with randomization to one of two accepted HIPEC treatment regimens

7-21 days hospitalization post-surgery

Inpatient stay for surgery and recovery

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of tumor response and quality of life

5 years

Every 3 months for 2 years, then every 6 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• 5-Fluorouracil
• Cisplatin
• Doxorubicin
• Heated Intraperitonial Chemotherapy
• Mitomycin C
• Oxaliplatin
• Sodium Thiosulfate

Trial Overview The trial is testing the effectiveness of heated chemotherapy (HIPEC) after tumor-removing surgery (CRS). Different chemo drugs are used based on a model called SMART System to see if they improve outcomes for patients with tumors spread within the abdomen lining.

How Is the Trial Designed?

Group I: 4/ HIPEC: Cisplatin, Mitomycin C Randomized treatment assignme Experimental Treatment 4 Interventions

HIPEC with intraperitoneal cisplatin and mitomycin C, in addition to IV sodium thiosulfate, randomly assigned

Group II: 3/ HIPEC: Cisplatin, Doxorubicin Randomized treatment assignme Experimental Treatment 4 Interventions

HIPEC with intraperitoneal cisplatin and doxorubicin, in addition to IV sodium thiosulfate, randomly assigned

Group III: 2/ HIPEC: Mitomycin C Randomized treatment assignment Experimental Treatment 2 Interventions

HIPEC with intraperitoneal mitomycin C, randomly assigned

Group IV: 1/ HIPEC: Oxaliplatin Randomized treatment assignment Experimental Treatment 3 Interventions

HIPEC with intraperitoneal oxaliplatin and IV 5-FU, randomly assigned

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Oxaliplatin degrades less in non-chloride carrier fluids compared to chloride-containing fluids, but the degradation rate remains low (10-15%) within 30 minutes, indicating that non-chloride solutions may help preserve the drug's effectiveness.

In both in vitro and in vivo studies, normal saline and Dianeal solutions showed higher absorption rates of oxaliplatin and acceptable degradation rates, suggesting they are more advantageous for use in oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) compared to 5% dextrose solution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo. Park, EJ., Ahn, J., Abuzar, SM., et al.[2022]

Continuous hyperthermic peritoneal perfusion (CHPP) of carboplatin (CBDCA) was safely administered to patients with small-volume residual ovarian cancer, with no core temperatures exceeding 40 degrees Celsius during treatment.

The study found that peak concentrations of platinum in the perfusate were significantly higher than in plasma, indicating a regional advantage for drug delivery, although dose-limiting hematologic toxicity was observed at higher doses (1200 mg/m2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer. Steller, MA., Egorin, MJ., Trimble, EL., et al.[2014]

In a study of 80 patients undergoing hyperthermic intraperitoneal chemotherapy (HIPC), those treated with oxaliplatin (OX) experienced significant electrolyte disturbances, including lower sodium levels and higher rates of hyponatremia compared to those treated with mitomycin C (MMC).

Despite these electrolyte issues, the overall complication rates and 30-day mortality were similar between the OX and MMC groups, indicating that while OX may cause predictable disturbances, it does not lead to worse outcomes if monitored and managed properly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C. Rueth, NM., Murray, SE., Huddleston, SJ., et al.[2018]

In a study involving nine patients, only 10-15% of the expected oxaliplatin (OX) was detected in peritoneal perfusates during hyperthermic intraperitoneal chemotherapy (HIPEC), indicating significant drug transformation and loss during treatment.

The cytotoxicity of the perfusates remained largely unchanged during HIPEC, suggesting that ex vivo bioactivity assays could be valuable for assessing the effectiveness of OX and its derivatives, potentially guiding future HIPEC protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols. Löffler, MW., Schuster, H., Zeck, A., et al.[2018]

In a study of 63 patients undergoing cisplatin (CDDP)-containing hyperthermic intraperitoneal chemotherapy (HIPEC), 66.1% experienced acute kidney injury (AKI), with the extent of parietal peritonectomy being a significant predictor of this complication.

Preclinical rat models showed that bilateral anterior parietal peritonectomy increased systemic absorption of CDDP by 1.6 to 2-fold, suggesting that careful consideration of CDDP dosage and concentration is crucial to minimize systemic toxicity and AKI risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extensive Peritonectomy is an Independent Risk Factor for Cisplatin HIPEC-Induced Acute Kidney Injury. Liesenfeld, LF., Quiring, E., Al-Saeedi, M., et al.[2023]

In a study of 145 patients with colorectal or appendiceal cancer, intraperitoneal doxorubicin showed significantly higher exposure to peritoneal surfaces (78 times greater) compared to plasma, indicating effective localized delivery of the drug.

Surgical factors, such as the extent of visceral resection and the size of the peritoneal space, significantly influenced doxorubicin clearance, suggesting that these factors should be considered when designing chemotherapy regimens for optimal efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of surgical and clinical factors on the pharmacology of intraperitoneal doxorubicin in 145 patients with peritoneal carcinomatosis. Sugarbaker, PH., Van der Speeten, K., Anthony Stuart, O., et al.[2013]

In a multicenter phase-I study involving 30 patients with initially unresectable ovarian cancer, the recommended dose of cisplatin for hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant chemotherapy was determined to be 70 mg/m², as higher doses led to significant dose-limiting toxicities (DLTs).

The study found that at the highest dose of 80 mg/m², there were serious adverse events including renal failure and hemorrhage, highlighting the importance of careful dose selection to minimize toxicity while maximizing treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer. Gouy, S., Ferron, G., Glehen, O., et al.[2022]

In a study of 53 patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin and doxorubicin, only 3.7% developed acute kidney injury (AKI), indicating a relatively low incidence of nephrotoxicity associated with this treatment.

However, there was a significant increase in hypomagnesemia, with levels dropping to 24.5% by day 7 and 30.1% by day 30 post-HIPEC, suggesting that monitoring magnesium levels is crucial after cisplatin administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery. Hakeam, HA., Breakiet, M., Azzam, A., et al.[2022]

The combination of mitomycin C, 5-fluorouracil, and oxaliplatin (MMC-5FU-OHP) demonstrated significant tumor-suppressive effects against colorectal cancer cells in vitro, especially under hyperthermic conditions, indicating its potential efficacy for HIPEC.

In a Phase I clinical study involving nine patients, HIPEC with MMC-5FU-OHP was found to be safe, with no dose-limiting toxicity observed, and the recommended dose of oxaliplatin was established at 130 mg/m².

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperthermic intraperitoneal chemotherapy using a combination of mitomycin C,5-fluorouracil, and oxaliplatin in patients at high risk of colorectal peritoneal metastasis: A Phase I clinical study. Shimizu, T., Sonoda, H., Murata, S., et al.[2018]

In a study involving 13 women with epithelial ovarian cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) using cisplatin and paclitaxel resulted in high drug concentrations in the peritoneal tissue while maintaining low levels in the bloodstream, indicating a favorable pharmacokinetic profile.

The treatment was associated with some surgical complications, with four patients experiencing grade 3-4 complications, but overall, HIPEC was deemed feasible and showed potential for effective localized treatment after cytoreductive surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer. Ansaloni, L., Coccolini, F., Morosi, L., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4302286/

Hyperthermic intraperitoneal chemotherapy with cisplatin ... CRS and HIPEC are associated to severe morbidity rate ranging from 12% to 52% [22], this percentage decreases in high volume specialized centers. In our ...

2. ar.iiarjournals.org ar.iiarjournals.org/content/42/2/1019

Hyperthermic Intraperitoneal Chemotherapy With Cisplatin ... Conclusion: HIPEC administered for 90 min is safe and does not increase perioperative morbidity and mortality compared to the 60-min administration. Key Words:.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0960740424000859

A Clinician's perspective on the role of hyperthermic ... The application of HIPEC may potentially enhance the survival rates of patients with OC, as indicated by a recent publication of high-quality prospective data.

4. sgo.org sgo.org/wp-content/uploads/2021/02/Charo-HIPEC.pdf

Charo-HIPEC.pdf The first three trials showed 20–40% reduction in death com- pared to intravenous (IV) chemotherapy alone in advanced stage ovarian cancer; the results of GOG ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04847063

Study Details | NCT04847063 | Individualized Response ... This is a Phase I study of cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), with randomization to one of two accepted HIPEC ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04213794?cond=%22Ovarian%20Cancer%22&intr=%22chelating%20agents%22&viewType=Table&rank=10

Study Details | Heated Intra-peritoneal Chemotherapy With ... This early phase I trial studies how well heated intra-peritoneal chemotherapy with doxorubicin and cisplatin work for the treatment of abdominal or pelvic ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6162496/

Heated Intraperitoneal Chemotherapy in the Management ... The majority of patients received cisplatin HIPEC (80.4%,) but 35.9% did receive a second agent with HIPEC, either doxorubicin (19.6%) or ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04213794

Study Details | Heated Intra-peritoneal Chemotherapy With ... This early phase I trial studies how well heated intra-peritoneal chemotherapy with doxorubicin and cisplatin work for the treatment of abdominal or pelvic ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10216120/

A Review of the Use of Hyperthermic Intraperitoneal ... Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to target microscopic peritoneal disease which can remain after visible disease has been surgically ...

10. mayoclinic.org mayoclinic.org/tests-procedures/hyperthermic-intraperitoneal-chemotherapy/about/pac-20583315

Hyperthermic intraperitoneal chemotherapy (HIPEC) HIPEC is a specialized cancer treatment used for cancers that have spread to the lining of the abdominal cavity, known as the peritoneum.