Repotrectinib + Chemotherapy for Cancer

Overseen By Emily Slotkin, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Bone marrow disease, Pregnancy, Infections, others

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

Compensation: Varies

Number of Visits: Unknown

77 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests the safety and effectiveness of repotrectinib combined with chemotherapy in children and young adults with severe, spreading cancer. The goal is to find the best dose with few side effects and see if it works well to stop cancer growth.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot use drugs that are strong CYP3A4 inhibitors or inducers. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug Repotrectinib + Chemotherapy for Cancer?

Irinotecan, a component of the treatment, has shown effectiveness in prolonging survival in patients with colorectal cancer resistant to other treatments, and it can be safely combined with other drugs for enhanced activity. ^{1 2 3 4 5}

Is the combination of Repotrectinib and chemotherapy safe for humans?

Irinotecan, a chemotherapy drug, can cause severe side effects, especially in people with certain genetic variations. Testing for these genetic markers can help predict and prevent these adverse reactions. ^{3 6 7 8 9}

What makes the drug Repotrectinib + Chemotherapy unique for cancer treatment?

Repotrectinib combined with chemotherapy, including Irinotecan and Temozolomide, is unique because it targets specific cancer pathways with a multitargeted approach, potentially offering a novel mechanism of action compared to standard treatments. This combination may provide an alternative for patients who do not respond well to existing therapies, such as those involving only Irinotecan or other chemotherapy agents. ^{4 5 10 11 12}

Research Team

Emily Slotkin, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for children and young adults with advanced or metastatic solid tumors who have not responded to standard therapy. They must have a certain level of physical ability, no severe infections, and meet specific blood count and organ function criteria. Pregnant individuals or those on strong CYP3A4 inhibitors are excluded.

Inclusion Criteria

My condition meets the specific criteria for this study.

I have recovered from side effects of my previous cancer treatments.

My brain tumor does not affect my daily activities much.

Exclusion Criteria

My condition worsened while I was being treated with irinotecan/temozolomide.

My neuroblastoma is only in my bone marrow and confirmed by a specific test.

Concurrent participation in another therapeutic clinical trial

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Part A: TPX-0005 (Repotrectinib) is administered orally once daily for 14 days, then increased to twice daily, with chemotherapy. Dose escalation follows a 'rolling 6' design.

8 weeks

Treatment Phase 2

Phase 2: Patients are treated at the recommended phase 2 dose of TPX-0005 (Repotrectinib) plus chemotherapy, determined in Phase 1.

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Treatment Details

Interventions

• Irinotecan and Temozolomide
• Repotrectinib

Trial Overview Researchers are testing the safety of repotrectinib combined with chemotherapy drugs irinotecan and temozolomide. The goal is to find the highest dose with minimal side effects, then see if it's effective against these types of cancers in youths.

Participant Groups

Group I: Phase II, Molecularly defined DSRCT Cohort Experimental Treatment 2 Interventions

Phase II, Molecularly defined DSRCT Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1

Group II: Phase II, Exploratory Cohort Experimental Treatment 2 Interventions

Phase II, Exploratory Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1

Group III: Phase II, DIPG Cohort Experimental Treatment 2 Interventions

Patients with DIPG will enroll in cohort 4 and receive TPX-0005 (Repotrectinib) monotherapy at the pediatric recommended phase 2 dose

Group IV: Phase II, ALK-mutated neuroblastoma Cohort (THIS IS CLOSED) Experimental Treatment 2 Interventions

Phase II, ALK-mutated neuroblastoma Cohort. Participants will be treated with the recommended phase 2 dose of TPX-0005 (Repotrectinib) + chemotherapy determined in Phase 1

Group V: Phase I portion Experimental Treatment 2 Interventions

Phase 1: Part A : TPX-0005 (Repotrectinib) will be given orally (without regard to food) once daily for 14 days, then increased to twice daily for remainder of cycles and concurrently administered with chemotherapy backbone described below. For patients less than 12 years old or less than 40kg, adult equivalent dosing (AED) will be used. Approximately 4-24 pediatric subjects will be enrolled into 2-4 dose levels (pending if DL-1 or DL-1b are utilized), with maximum of 6 subjects per dose level according to the 'rolling 6' design. Starting dose of TPX-0005 (Repotrectinib) will begin at dose level (DL) 1. Part B (combination therapy; patients less than 12 years old or ≤ 50kg): For 6 additional patients, a safety run-in will be conducted with TPX-0005 (Repotrectinib) and chemotherapy.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

Regorafenib, an oral multikinase inhibitor, significantly improves progression-free survival and overall survival in patients with chemorefractory metastatic colorectal cancer, making it a valuable treatment option.

This study highlights the potential of using PD-L1 expression on circulating tumor cells as a predictive biomarker for response to regorafenib, suggesting that monitoring this biomarker could help tailor more effective, individualized treatment plans for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 Expression on Circulating Tumour Cells May Be Predictive of Response to Regorafenib in Patients Diagnosed with Chemorefractory Metastatic Colorectal Cancer. Raimondi, L., Raimondi, FM., Di Benedetto, L., et al.[2021]

The study identified DCR1 promoter hypermethylation as a potential predictive biomarker for the effectiveness of irinotecan combined with capecitabine in metastatic colorectal cancer, showing that patients with unmethylated DCR1 had significantly better outcomes.

However, the results could not be replicated in an external validation set for irinotecan combined with 5FU, highlighting the need for further clinical evaluation of biomarkers across different treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer. Bosch, LJW., Trooskens, G., Snaebjornsson, P., et al.[2019]

In a study of 41 patients with heavily treated metastatic colorectal cancer, the combination of regorafenib and dose-escalated irinotecan (FOLFIRI) showed a disease control rate of 58.5%, with median progression-free survival of 6.0 months and overall survival of 12.0 months, indicating promising efficacy.

KRAS mutations and positive EGFR expression were associated with poorer outcomes, while left-sided tumors were linked to better survival rates, suggesting that tumor sidedness could be an important factor in predicting treatment response to this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting. Ma, CJ., Huang, CW., Chang, TK., et al.[2023]

In a study involving 335 tumor specimens from patients with metastatic colorectal cancer, the advanced colorectal cancer subtype (aCRCS) was identified as a potential biomarker to help decide whether to use oxaliplatin (OX) or irinotecan (IRI) as the first-line treatment.

Patients classified as aCRCS A1 + B1 showed significantly better progression-free survival (PFS) with IRI compared to OX, indicating that nearly 47% of these patients respond well to IRI, while only about 18.5% of aCRCS B2 patients responded well to OX.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced colorectal cancer subtypes (aCRCS) help select oxaliplatin-based or irinotecan-based therapy for colorectal cancer. Takahashi, S., Sakamoto, Y., Denda, T., et al.[2021]

Irinotecan has been shown to significantly prolong survival in patients with 5-FU-resistant colorectal cancer compared to best supportive care or 5-FU-based chemotherapy, based on Phase III studies.

Combining irinotecan with other treatments, such as raltitrexed or oral fluoropyrimidines, has shown promising results in terms of safety and efficacy, with response rates exceeding 30% and median survival benefits in various cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies. Armand, JP., Cunningham, D., van Cutsem, E., et al.[2019]

New treatments like regorafenib and TAS-102 have been shown to improve progression-free survival and overall survival in patients with heavily pretreated metastatic colorectal cancer, leading to their approval in the U.S. and globally.

The study highlights the importance of evaluating both the benefits and toxicities of these new agents, as they are used after standard chemotherapy and targeted therapies in patients with RAS wild-type tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Therapies After Standard Combination Regimens. Chokshi, S., Hochster, HS.[2020]

In a phase II trial involving 48 patients with untreated advanced colorectal cancer, the combination of irinotecan and raltitrexed showed an overall response rate of 27%, with a median duration of response of 10 months.

Despite its activity, the treatment was associated with significant side effects, including grade III-IV diarrhea and neutropenia, leading to a dose reduction and highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. Chiara, S., Nobile, MT., Tomasello, L., et al.[2018]

In a study of 36 patients with advanced non-small cell lung cancer (NSCLC), the combination of irinotecan and cisplatin showed a partial response rate of 22.9% and a stable disease rate of 60%, indicating its efficacy in this patient population.

The treatment was associated with manageable adverse events, with grade III/IV side effects occurring in a minority of patients, including neutropenia (16.7%) and alopecia (13.9%), suggesting that the regimen is tolerable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Irinotecan plus cisplatin for the treatment of advanced non-small cell lung cancer]. Zhang, XR., Zhu, YZ., Xiu, QY., et al.[2018]

In a study of 158 patients with metastatic colorectal cancer, specific genetic variations (SNPs) in the ABCB1 gene were found to significantly predict the risk of severe adverse reactions to irinotecan, a common chemotherapy drug.

Genotyping these ABCB1 variants can help identify patients at higher risk for hematological and overall toxicity, potentially allowing for better management of treatment and improved patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan. Salvador-Martín, S., García-González, X., García, MI., et al.[2019]

In a study involving 45 patients with metastatic colorectal cancer, the combination of regorafenib with standard chemotherapy showed acceptable tolerability, with most adverse events being manageable, particularly neutropenia and leukopenia.

Out of the patients treated, 33 achieved disease control (either partial response or stable disease) for a median duration of 126 days, indicating that regorafenib can enhance treatment effectiveness when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Schultheis, B., Folprecht, G., Kuhlmann, J., et al.[2021]

This study aims to evaluate the efficacy and safety of a combination treatment of dose-adjusted regorafenib and FOLFIRI in patients with metastatic colorectal cancer (mCRC), focusing on progression-free survival as the primary endpoint.

By adjusting the doses of regorafenib and irinotecan based on individual genetic factors, the study seeks to reduce treatment-related adverse events, making the combination therapy more tolerable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1genotyping in previous treated metastatic colorectal cancer patients:study protocol for a randomized controlled trial. Ma, CJ., Chang, TK., Tsai, HL., et al.[2020]

A new biomarker, aprataxin (APTX), has been identified that correlates with the sensitivity of colorectal cancer cells to irinotecan, suggesting it could help predict which patients are likely to respond to this treatment.

In a study of 135 colorectal cancer patients, those with low levels of aprataxin in their tumors had significantly longer progression-free and overall survival compared to those with high aprataxin levels, indicating that aprataxin levels could guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. Dopeso, H., Mateo-Lozano, S., Elez, E., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

PD-L1 Expression on Circulating Tumour Cells May Be Predictive of Response to Regorafenib in Patients Diagnosed with Chemorefractory Metastatic Colorectal Cancer. [2021]

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

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer. [2019]

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

Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting. [2023]

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

Advanced colorectal cancer subtypes (aCRCS) help select oxaliplatin-based or irinotecan-based therapy for colorectal cancer. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies. [2019]

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

Single-Agent Therapies After Standard Combination Regimens. [2020]

7. Greece pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. [2018]

8. China pubmed.ncbi.nlm.nih.gov

[Irinotecan plus cisplatin for the treatment of advanced non-small cell lung cancer]. [2018]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1genotyping in previous treated metastatic colorectal cancer patients:study protocol for a randomized controlled trial. [2020]

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

Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. [2018]