Repotrectinib for Solid Tumors

(TRIDENT-1 Trial)

Recruiting in Palo Alto (17 mi)

+377 other locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Turning Point Therapeutics, Inc.

Disqualifiers: Symptomatic brain metastases, Cardiovascular disease, Active infections, others

No Placebo Group

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction. Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you cannot participate in another therapeutic clinical trial at the same time, and certain heart medications might be a concern due to potential heart-related side effects.

What data supports the effectiveness of the drug Repotrectinib (TPX-0005) for solid tumors?

Research shows that Repotrectinib is effective in treating cancers with specific genetic changes, like ROS1, ALK, and NTRK mutations, especially when other treatments stop working. It has shown strong antitumor effects in neuroblastoma and lung cancer models, even overcoming certain resistance mutations.

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Is Repotrectinib safe for human use?

Repotrectinib has been tested in early-phase clinical trials and has shown confirmed responses in patients with certain types of cancer, indicating it is generally safe for human use. However, as with any medication, there may be side effects, and its safety profile is still being evaluated in ongoing studies.

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What makes the drug Repotrectinib unique for treating solid tumors?

Repotrectinib is a next-generation drug that targets specific mutations in cancer cells, making it effective against tumors that have become resistant to earlier treatments. It is particularly potent against mutations in ROS1, TRK, and ALK genes, which are common in certain types of cancer, and it can overcome resistance caused by these mutations, offering a new option for patients who have relapsed on other therapies.

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Eligibility Criteria

Adults with advanced solid tumors that have specific gene rearrangements (ALK, ROS1, NTRK1-3) can join this trial. They should have at least one measurable tumor and a life expectancy of over 3 months. Prior cancer treatments are okay if side effects are minimal now. People with certain heart conditions, active infections, significant lung disease or recent major surgery cannot participate.

Inclusion Criteria

My cancer is advanced and tests show specific gene changes.

I am at least 18 years old, or 20 if required by local laws.

I can swallow pills without breaking them.

Exclusion Criteria

I have had cancer before, but it was either skin cancer treated successfully or another type that was completely removed and didn’t need treatment in the last 2 years.

I do not have moderate or severe numbness, tingling, or pain in my hands or feet.

I haven't had radiation therapy (except for bone pain relief) in the last 2 weeks.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Phase 1 dose escalation to determine dose-limiting toxicities, maximum tolerated dose, and recommended Phase 2 dose of repotrectinib

4 weeks

Multiple visits for dose escalation and monitoring

Phase 2 Treatment

Phase 2 to determine the confirmed Overall Response Rate (ORR) and other secondary outcomes in expansion cohorts

Approximately 2-3 years

Regular visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

Participant Groups

The study is testing the safety and effectiveness of an oral drug called repotrectinib in two phases: first to find the safest dose and then to see how well it works against tumors. It also looks into how repotrectinib affects another drug's breakdown in the body.

Group I: Repotrectinib (TPX-0005) Experimental Treatment 1 Intervention

Phase 1 Oral repotrectinib (TPX-0005): Phase 1a dose escalation, Phase 1b food-effect sub-study, and Phase 1c dose escalation with food, and Midazolam drug-drug interaction sub-study. Phase 2 Oral repotrectinib (TPX-0005): 6 distinct expansion cohorts * EXP-1: ROS1 TKI-naïve ROS1+ NSCLC * EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC * EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) * EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) * EXP-5: TRK TKI-naïve NTRK+ solid tumors * EXP-6: TRK TKI-pretreated NTRK+ solid tumors

Repotrectinib (TPX-0005) is already approved in United States for the following indications:

🇺🇸 Approved in United States as Augtyro for:

• Locally advanced or metastatic ROS1-positive non-small cell lung cancer

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

City of Hope PHASE 2 Duarte, CA

Adventist Health Glendale PHASE 2 Glendale, CA

University Cancer and Blood Center PHASE 2 Athens, GA

Ventura County Hematology Oncology Specialists PHASE 2 Oxnard, CA

More Trial Locations

Who Is Running the Clinical Trial?

Turning Point Therapeutics, Inc. Lead Sponsor

Zai Lab (Shanghai) Co., Ltd. Industry Sponsor

References

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

Novel Human-Derived RET Fusion NSCLC Cell Lines Have Heterogeneous Responses to RET Inhibitors and Differential Regulation of Downstream Signaling. [2021] Rearranged during transfection (RET) rearrangements occur in 1% to 2% of lung adenocarcinomas as well as other malignancies and are now established targets for tyrosine kinase inhibitors. We developed three novel RET fusion-positive (RET+) patient-derived cancer cell lines, CUTO22 [kinesin 5B (KIF5B)-RET fusion], CUTO32 (KIF5B-RET fusion), and CUTO42 (echinoderm microtubule-associated protein-like 4-RET fusion), to study RET signaling and response to therapy. We confirmed each of our cell lines expresses the RET fusion protein and assessed their sensitivity to RET inhibitors. We found that the CUTO22 and CUTO42 cell lines were sensitive to multiple RET inhibitors, whereas the CUTO32 cell line was >10-fold more resistant to three RET inhibitors. We discovered that our RET+ cell lines had differential regulation of the mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B (AKT) pathways. After inhibition of RET, the CUTO42 cells had robust inhibition of phosphorylated AKT (pAKT), whereas CUTO22 and CUTO32 cells had sustained AKT activation. Next, we performed a drug screen, which revealed that the CUTO32 cells were sensitive (<1 nM IC50) to inhibition of two cell cycle-regulating proteins, polo-like kinase 1 and Aurora kinase A. Finally, we show that two of these cell lines, CUTO32 and CUTO42, successfully establish xenografted tumors in nude mice. We demonstrated that the RET inhibitor BLU-667 was effective at inhibiting tumor growth in CUTO42 tumors but had a much less profound effect in CUTO32 tumors, consistent with our in vitro experiments. These data highlight the utility of new RET+ models to elucidate differences in response to tyrosine kinase inhibitors and downstream signaling regulation. Our RET+ cell lines effectively recapitulate the interpatient heterogeneity observed in response to RET inhibitors and reveal opportunities for alternative or combination therapies. SIGNIFICANCE STATEMENT: We have derived and characterized three novel rearranged during transfection (RET) fusion non-small cell lung cancer cell lines and demonstrated that they have differential responses to RET inhibition as well as regulation of downstream signaling, an area that has previously been limited by a lack of diverse cell line modes with endogenous RET fusions. These data offer important insight into regulation of response to RET tyrosine kinase inhibitors and other potential therapeutic targets.

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

Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. [2023] Label="PURPOSE">Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models.

3. England pubmed.ncbi.nlm.nih.gov

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells. [2021] Neuroblastoma is the most commonly diagnosed extracranial tumor in the first year of life. Approximately 9% of neuroblastoma patients present germline or somatic aberrations in the gene encoding for anaplastic lymphoma kinase (ALK). This increases in high-risk neuroblastomas, which have a 14% frequency of ALK aberrations at the time of diagnosis and show increasing numbers at relapse. Abrogating ALK activity with kinase inhibitors is employed as clinical therapy in malignancies such as non-small cell lung cancer and has shown good results in pediatric inflammatory myofibroblastic tumors and anaplastic large cell lymphomas. A phase I clinical trial of the first generation ALK inhibitor, crizotinib, in neuroblastoma patients showed modest results and suggested that further investigation was needed. Continuous development of ALK inhibitors has resulted in the third generation inhibitor repotrectinib (TPX-0005), which targets the active kinase conformations of ALK, ROS1 and TRK receptors. In the present study we investigated the effects of repotrectinib in a neuroblastoma setting in vitro and in vivo. Neuroblastoma cell lines were treated with repotrectinib to investigate inhibition of ALK and to determine its effect on proliferation. PC12 cells transfected with different ALK mutant variants were used to study the efficacy of repotrectinib to block ALK activation/signaling. The in vivo effect of repotrectinib was also analyzed in a neuroblastoma xenograft model. Our results show that repotrectinib is capable of inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and importantly it exhibits strong antitumor effects in a xenograft model of neuroblastoma.

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

Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. [2022] The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA-C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1-3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA-C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion-positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance.Significance: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1-3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1227-36. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.

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

Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report. [2023] ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

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

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. [2022] Label="PURPOSE">Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in ROS1 fusion-positive NSCLC.

7. China pubmed.ncbi.nlm.nih.gov

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond? [2020] ROS1-rearranged (also known as ROS1 fusion-positive) non-small-cell lung cancer is an uncommon but distinct molecular subgroup seen in approximately 1-2% of cases. Oncogene addiction due to constitutive ROS1 tyrosine kinase activation has allowed development of molecularly targeted therapies with remarkable anti-tumor activity. Both crizotinib and entrectinib, multitargeted tyrosine kinase inhibitors (TKIs) have now received approval by the FDA for treatment of patients with advanced ROS1-rearranged lung cancers; however, the clinical efficacy and safety of these drugs have been derived from expansion cohorts of single-arm phase I or basket clinical trials with relatively small populations of this clinically and molecularly distinct subgroup. Both drugs lead to high objective response rates (approximately 70-80%) and have manageable side effects, although only entrectinib has potent intracranial efficacy. Lorlatinib is an oral brain-penetrant ALK/ROS1 TKI with activity in both TKI-naïve and some crizotinib-resistant settings (albeit with limited potency against the crizotinib/entrectinib-resistant ROS1-G2032R mutation). We describe cases of advanced ROS1-rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1-G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.