Repotrectinib + Chemotherapy for Cancer
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: CYP3A4 inhibitors/inducers
Disqualifiers: Bone marrow disease, Pregnancy, Infections, others
No Placebo Group
Breakthrough Therapy
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.
12345Is 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.
36789What 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.
45101112Eligibility 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.
+10 more
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
+10 more
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
Participant Groups
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.
5Treatment groups
Experimental Treatment
Group I: Phase II, Molecularly defined DSRCT CohortExperimental Treatment2 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 CohortExperimental Treatment2 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 CohortExperimental Treatment2 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 CohortExperimental Treatment2 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 portionExperimental Treatment2 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 50kg, 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Cancer Center (All Protocol Activities)New York, NY
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
References
PD-L1 Expression on Circulating Tumour Cells May Be Predictive of Response to Regorafenib in Patients Diagnosed with Chemorefractory Metastatic Colorectal Cancer. [2021]Regorafenib, targeting a broad range of receptor tyrosine kinases (RTKs), is an oral multikinase inhibitor which improves the progression-free survival (PFS) and overall survival (OS) of patients diagnosed with chemorefractory metastatic colorectal cancer (mCRC), making an immunosuppressive tumour microenvironment. The correlation between PD-1/PD-L1 expression and RTKs inhibition has been studied in several tumour types but has not been analyzed extensively in mCRC in the era of regorafenib. In this study, using liquid biopsy, we evaluated the opportunity to reveal if PD-L1 expression on circulating tumour cells (CTCs) could serve as a predictive biomarker of response and clinical benefit in patients treated with regorafenib as the third line of treatment. We analyzed a cohort of forty chemorefractory metastatic colorectal cancer patients, of whom twenty-six KRAS mutated, treated with regorafenib, all as the third line of treatment. Blood samples were collected from patients prior to treatment and longitudinally four and eight weeks after initiation of therapy. CTCs were identified using multiparametric flow cytometry; therefore, PD-L1 expression was evaluated. Objective responses were defined following the RECIST criteria v.1.1. Moreover, focusing on peripheral blood biomarkers, we found that high platelet-to-lymphocyte ratio (PLR) was an independent prognostic indicator of poor OS. For the first time, our study showed the usefulness of sequential assessments of CTCs as a non-invasive real-time biopsy to evaluate PD-L1 expression in patients diagnosed with mCRC and treated with regorafenib. Our analysis suggests that by assessing PD-L1 expression on CTCs, we could predict who will benefit from regorafenib, offering highly individualized treatment plans.
Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer. [2019]Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials.
Oncologic Outcomes in Metastatic Colorectal Cancer with Regorafenib with FOLFIRI as a Third- or Fourth-Line Setting. [2023]To evaluate the efficacy and toxicities of regorafenib plus irinotecan, dose-escalated on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping, in previously heavily treated metastatic colorectal cancer (mCRC) and the prognostic values of EGFR expression, KRAS mutations, and tumor sidedness.
Advanced colorectal cancer subtypes (aCRCS) help select oxaliplatin-based or irinotecan-based therapy for colorectal cancer. [2021]Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first-line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin-fixed, paraffin-embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC-related genes, comprehensive gene-expression analysis, and genome-wide methylation analysis. The progression-free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild-type (WT), PTEN-positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41-0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94-2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX-based and IRI-based therapies.
Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies. [2019]Phase III studies have shown irinotecan prolongs survival significantly when compared with either best supportive care or best infusional 5-fluorouracil (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal cancer. Phase I/II studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with the oral fluoropyrimidines. Preliminary results suggest irinotecan and raltitrexed can safely be combined in the clinic and that this combination is active. The combination of irinotecan with the oral fluoropyrimidines also has produced promising results. A phase I study of irinotecan plus 5-FU/folinic acid showed high activity in first-line metastatic disease and further trials using the doses of 80 mg/m2 irinotecan plus 2 g 5-FU weekly are recommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Alternating exposure to irinotecan and 5-FU may be as active as either treatment alone, and has been associated with overall response rates (ORRs) greater than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the region of 50% (especially with a 2-weekly administration schedule). In patients with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either cisplatin plus irinotecan or cisplatin plus docetaxel.
Single-Agent Therapies After Standard Combination Regimens. [2020]Increasingly prolonged survival in metastatic colorectal cancer has paralleled the approval of new agents alone and in combination. Most recently, several new agents have sought approval in the heavily pretreated setting, after treatment with standard chemotherapies, alone and in combination, and with anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor (for patients with RAS wild-type tumors). These agents have included the multitargeted tyrosine kinase inhibitor (TKI), regorafenib, and the novel antimetabolite combination, TAS-102. Both of these showed improvement in progression-free survival and overall survival compared with placebo controls and were approved in the United States and the rest of the world. Benefits of treatment and toxicities are discussed. Nintedanib, another multitargeted TKI, is already approved by the European Medicines Evaluation Agency for non-small cell lung cancer and has been studied in a similar phase III trial. Results are pending. The risks and benefits of each agent are discussed.
Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. [2018]Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC.
[Irinotecan plus cisplatin for the treatment of advanced non-small cell lung cancer]. [2018]To evaluate the efficacy and adverse events of irinotecan (CPT-11) combined with cisplatin (DDP) in the treatment of patients with advanced non-small cell lung cancer (NSCLC).
Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan. [2019]Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.
Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. [2021]Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective).
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]Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC.
Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. [2018]Irinotecan (CPT11) treatment significantly improves the survival of colorectal cancer patients and is routinely used for the treatment of these patients, alone or in combination with other agents. However, only 20% to 30% of patients show an objective response to irinotecan, and there is great need for new molecular markers capable of identifying the subset of patients who are unlikely to respond.