Lurbinectedin + Irinotecan for Cancer

Recruiting at21 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: PharmaMar

Must not be taking: Topoisomerase inhibitors

Disqualifiers: Heart disease, Uncontrolled infection, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Prospective, open-label, dose-ranging, uncontrolled phase I/II study of Lurbinectedin in combination with irinotecan. The study will be divided into two stages: a Phase I dose escalation stage and a Phase II expansion stage.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement to wait at least three weeks after your last anticancer therapy before starting the trial, and certain exceptions apply for specific drugs. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Lurbinectedin and Irinotecan for cancer?

Irinotecan has shown activity against various cancers, including colorectal, lung, and other gastrointestinal cancers, as well as lymphoma and leukemia. It has been used in combination with other drugs to improve treatment outcomes in some cases. ^{1 2 3 4 5}

What safety information is available for the cancer treatment using Lurbinectedin and Irinotecan?

Irinotecan, also known as Camptosar, has been studied extensively and is known to cause side effects like neutropenia (low white blood cell count) and diarrhea, which can limit its use. These side effects have been observed in various cancer treatments, including colorectal cancer, and managing them is an important part of its clinical use. ^{3 5 6 7 8}

What makes the drug combination of Lurbinectedin and Irinotecan unique for cancer treatment?

The combination of Lurbinectedin and Irinotecan is unique because it pairs two drugs with different mechanisms of action: Lurbinectedin, which interferes with cancer cell DNA, and Irinotecan, a derivative of camptothecin that inhibits DNA replication. This combination may offer a novel approach for treating cancers that have not responded well to other treatments. ^{3 5 6 9 10}

Research Team

Eligibility Criteria

Adults with certain advanced solid tumors who've had a break from cancer treatments for at least three weeks, are in fairly good health (ECOG ≤ 1), and have a life expectancy of over three months. They must not be pregnant or breastfeeding and should use effective contraception. Excluded are those with active COVID-19, prior significant bone marrow treatments, known brain metastases, or allergies to study drugs.

Inclusion Criteria

At least three weeks since the last anticancer therapy, (including immunotherapy, investigational drugs and radiotherapy), and at least six weeks since nitrosoureas and mitomycin C (systemic)

Voluntarily signed and dated written informed consent prior to any specific-study procedure

Age ≥ 18 years

Exclusion Criteria

Active Coronavirus disease (COVID-19) (this includes positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR)

Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow

Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Dose Escalation

Patients with selected advanced solid tumors are divided into three groups for dose escalation to determine the Maximum Tolerated Dose (MTD).

3 weeks per cycle

Multiple visits per cycle for dose administration and monitoring

Phase II Expansion

Tumor-specific expansion cohorts are treated at the Recommended Dose (RD) to evaluate efficacy in specific tumor types.

66 months

Regular visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months after the inclusion of the last evaluable patient

Treatment Details

Interventions

• Irinotecan (Topoisomerase I inhibitors)
• Lurbinectedin (Alkylating agents)

Trial Overview This is an early-phase trial testing the combination of two cancer drugs: Lurbinectedin and Irinotecan. It's divided into two parts: first finding the right doses (Phase I) and then expanding to more patients at that dose (Phase II).

Participant Groups

Group I: Lurbinectedin Escalation Group Experimental Treatment 2 Interventions

Irinotecan 75 mg/m\^2 as a 90-min (-5-min/+30-min) intravenous (i.v.) infusion, followed by Lurbinectedin with starting dose of 1.0 mg/m\^2 as a 60-min (-5-min/+20-min) i.v. infusion followed by Irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min \[-5-min/+30-min\] i.v. infusion)

Group II: Irinotecan Escalation Group Experimental Treatment 2 Interventions

Starting dose of Irinotecan 15 mg/m\^2 as a 90-min (-5-min/+30-min) i.v. infusion, followed by Lurbinectedin 3.0 mg/m\^2 as a 60-min (-5-min/+20-min) i.v. infusion followed by Irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min \[-5-min/+30-min\] i.v. infusion).

Group III: Intermediate Escalation Group Experimental Treatment 2 Interventions

Starting dose of Irinotecan 50 mg/m\^2 as a 90-min (-5-min/+30-min) i.v. infusion, followed by Lurbinectedin 2.6 mg/m\^2 as a 60-min (-5-min/+20-min) i.v. infusion. No Irinotecan dose will be administered on Day 8 in this group.

Irinotecan is already approved in Japan, Canada for the following indications:

Approved in Japan as Topotecin for:

• Colorectal cancer
• Small cell lung cancer

Approved in Canada as Irinotecan for:

• Colorectal cancer

Who Is Running the Clinical Trial?

PharmaMar

Lead Sponsor

Trials

93

Recruited

11,800+

José María Fernández de Sousa-Faro

PharmaMar

Chief Executive Officer since 1986

PhD in Biochemistry, Complutense University of Madrid

Carmen Cuevas Marchante

PharmaMar

Chief Medical Officer since 2002

MD, University of Navarra

Findings from Research

Irinotecan is approved as a second-line treatment for metastatic colorectal cancer and has shown promising single-agent activity in Phase II studies for first-line treatment, with response rates comparable to standard regimens.

Due to its high cost and lack of definitive evidence showing superiority over current first-line treatments, routine use of irinotecan as a single agent may not be justified, although combination therapies with fluorouracil and molecular markers could help identify suitable patients for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in the first-line treatment of colorectal cancer. Saltz, LB.[2018]

In a study of 61 patients with metastatic non-small-cell lung cancer (NSCLC), the combination of irinotecan (CPT-11) and etoposide (VP-16) resulted in a modest overall response rate of 21.3%, with a median survival time of 10 months.

The treatment was associated with manageable toxicities, including significant hematologic side effects like leukopenia and neutropenia in 23% and 39% of patients, respectively, but was comparable in efficacy to standard cisplatin-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer. Oshita, F., Noda, K., Nishiwaki, Y., et al.[2018]

Irinotecan (CPT-11) demonstrated activity in treating recurrent malignant gliomas, with 15% of patients showing a confirmed partial response and 55% achieving stable disease for over 12 weeks, based on a study of 60 patients.

The treatment was associated with limited toxicity, primarily mild side effects like neutropenia and nausea, but the low plasma concentrations of the drug suggest that concurrent use of anticonvulsants and dexamethasone may reduce its effectiveness by enhancing drug clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan therapy in adults with recurrent or progressive malignant glioma. Friedman, HS., Petros, WP., Friedman, AH., et al.[2022]

Irinotecan has been extensively evaluated since its approval in 1996, with recent studies focusing on its use in combination chemotherapy regimens for treating colorectal and other gastrointestinal cancers, as well as lung cancers.

Research over the past five years has provided valuable insights into irinotecan's pharmacology, metabolism, and mechanisms of resistance, enhancing our understanding of how to optimize its use in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan (CPT-11): recent developments and future directions--colorectal cancer and beyond. Rothenberg, ML.[2019]

Irinotecan (CPT-11) has demonstrated a broad range of antitumor activity across various cancer types, including lymphoma, leukemia, and several solid tumors, although most studies have focused on colorectal and gastrointestinal cancers.

Preliminary results indicate that irinotecan shows modest but reproducible activity in multiple cancers, suggesting the need for further well-designed clinical trials to better understand its efficacy and optimal use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Rosen, LS.[2018]

Irinotecan is an approved treatment for colorectal cancer that does not respond to fluorouracil, highlighting its role in managing difficult cases of this disease.

The review addresses the drug's toxicity and management strategies, indicating that while irinotecan is effective, careful monitoring and handling of side effects are crucial for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Use of Irinotecan: Current Status and Future Considerations. Saltz, LB.[2019]

Irinotecan has shown significant activity against advanced colorectal cancer when combined with traditional chemotherapy agents like fluorouracil, leading to clinical responses including complete remissions in patients.

The combination therapies have acceptable toxicity profiles, with neutropenia and delayed diarrhea being the most common side effects, indicating that irinotecan could be a safe option for treatment, although further large-scale phase III studies are needed to confirm its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. Khayat, D., Gil-Delgado, M., Antoine, EC., et al.[2018]

Irinotecan, a semisynthetic version of camptothecin, has shown promising activity in treating lung cancer, which has seen stagnant survival rates over the past 20 years.

The article reviews the mechanism of action and development history of irinotecan, highlighting its potential as a new treatment option for lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of irinotecan in lung cancer. Fukuoka, M.[2018]

Irinotecan, a derivative of camptothecin, shows promise when used in combination with fluorouracil (5-FU) for preoperative treatment of advanced rectal cancer, potentially enhancing treatment effectiveness.

The review discusses how both fluoropyrimidines and camptothecin can sensitize cancer cells to radiation, supporting the rationale for using these drugs together in combined-modality therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan in preoperative combined-modality therapy for locally advanced rectal cancer. Mitchell, EP.[2018]

References

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

Irinotecan in the first-line treatment of colorectal cancer. [2018]

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

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer. [2018]

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

Irinotecan therapy in adults with recurrent or progressive malignant glioma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Irinotecan (CPT-11): recent developments and future directions--colorectal cancer and beyond. [2019]

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

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Clinical Use of Irinotecan: Current Status and Future Considerations. [2019]

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

European experience with irinotecan plus fluorouracil/folinic acid or mitomycin. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Insight into the mechanism of Xiao-Chai-Hu-Tang alleviates irinotecan-induced diarrhea based on regulating the gut microbiota and inhibiting Gut β-GUS. [2023]

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

Current status of irinotecan in lung cancer. [2018]

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

Irinotecan in preoperative combined-modality therapy for locally advanced rectal cancer. [2018]