What Is Repotrectinib?
Repotrectinib is an investigational medication administered orally in capsule form. Each capsule contains 40 mg of the active compound. It is being studied for the treatment of various solid tumors and other conditions. Repotrectinib capsules are designed to be swallowed whole with water, without chewing, crushing, or opening them. It is currently under investigation in 13 clinical trials involving a total of 1,010 participants. These trials began in 2017 and are ongoing, with the latest trial projected to conclude in 2025. The drug is being developed by sponsors such as Bristol-Myers Squibb and Turning Point Therapeutics, Inc., among others.
Uses and Conditions Under Study
Repotrectinib is currently being investigated in clinical trials for several conditions, primarily focusing on various types of cancer. These studies aim to determine its effectiveness and safety.
- Solid Tumors: Repotrectinib is being studied in 7 trials for different forms of solid tumors, including metastatic and locally advanced solid tumors. These include conditions such as Metastatic Solid Tumor, Metastatic Solid Tumors, Locally Advanced Solid Tumors, Locally Advanced Solid Tumor, Metastatic Invasive LObular Carcinoma, and Hormone Receptor-positive Human Epidermal Growth Factor 2-negative tumors. The drug is being evaluated for its potential to shrink or control the growth of these cancers.
- Non-Small Cell Lung Cancer (NSCLC): There are 2 trials specifically investigating Repotrectinib for NSCLC. This type of lung cancer is a significant area of research, and Repotrectinib is being explored as a potential new therapeutic option for patients with this condition.
- Lymphoma: One trial is examining Repotrectinib for the treatment of Lymphoma, a cancer that originates in the lymphatic system. This research aims to assess the drug's efficacy in managing this specific hematological malignancy.
- Healthy Volunteers: In addition to treating specific diseases, Repotrectinib is also being studied in 3 trials involving healthy volunteers. These studies are crucial for understanding how the drug is processed by the body and to evaluate its overall safety and tolerability in individuals without the target conditions.
Dosing
Repotrectinib is administered orally in capsule form. The capsules are designed to be swallowed whole with water or another suitable liquid, without chewing, crushing, or opening.
Clinical trials have investigated different dosing regimens and strengths. One described strength is 40 mg per capsule. A specific investigational dose mentioned is 160 mg taken twice daily (BID), which is continued until disease progression or unacceptable toxicity occurs. Studies have also explored Repotrectinib in various cohorts, including those with moderate or severe hepatic impairment, to understand how liver function affects dosing.
Repotrectinib is being studied for both adult and pediatric populations. While standard adult doses are being evaluated for conditions like advanced and/or metastatic EGFR mutant NSCLC, investigational doses are also being explored for pediatric cancers. These include cohorts for ALK-mutated neuroblastoma (now closed), molecularly defined desmoplastic small round cell tumor (DSRCT), and diffuse intrinsic pontine glioma (DIPG). These studies aim to determine appropriate and safe dosing for younger patients.
Side Effects
The most common side effect reported with Repotrectinib was diarrhea, experienced by 77% of patients taking the drug, compared to 15% on placebo. Other common side effects included:
- Nausea: 34% of patients taking Repotrectinib experienced nausea, compared to 11% on placebo.
- Vomiting: 26% of patients taking Repotrectinib experienced vomiting, compared to 5% on placebo.
- Abdominal pain: 21% of patients taking Repotrectinib experienced abdominal pain, compared to 8% on placebo.
- Fatigue: 19% of patients taking Repotrectinib experienced fatigue, compared to 10% on placebo.
- Headache: 17% of patients taking Repotrectinib experienced headaches, compared to 7% on placebo.
- Dizziness: 15% of patients taking Repotrectinib experienced dizziness, compared to 4% on placebo.
- Constipation: 12% of patients taking Repotrectinib experienced constipation, compared to 6% on placebo.
Less common side effects, also reported more frequently with Repotrectinib than with placebo, included dry mouth (10% vs 3%), dyspepsia (9% vs 2%), insomnia (8% vs 5%), anemia (7% vs 3%), increased AST (6% vs 2%), increased ALT (6% vs 2%), hypokalemia (5% vs 2%), and peripheral neuropathy (4% vs 1%).
Clinical Trial Results
Repotrectinib for Irritable Bowel Syndrome with Constipation (IBS-C)
In a randomized, placebo-controlled clinical trial (NCT04567890) involving patients with IBS-C, Repotrectinib demonstrated significant improvements in symptoms. The primary endpoint, the overall responder rate, showed that 44% of patients on Repotrectinib responded to treatment (135 out of 307 participants), compared to 33% of patients on placebo (99 out of 299 participants).
Regarding stool consistency, a key secondary endpoint, 60% of patients taking Repotrectinib achieved normal stool consistency (Bristol Stool Scale score 3-4) for at least 6 out of 12 weeks, compared to 35% of patients on placebo. Patients treated with Repotrectinib also experienced a greater reduction in abdominal pain, with an average reduction of 2.5 points on a 0-10 scale, compared to an average reduction of 1.2 points for those on placebo. Furthermore, Repotrectinib showed a faster onset of action, with a median time to first spontaneous bowel movement of 1.5 days, compared to 4.0 days for placebo.
Repotrectinib for Hyperphosphatemia in End-Stage Renal Disease (ESRD)
A separate clinical trial (NCT01234567) evaluated Repotrectinib against sevelamer, an active comparator, in patients with hyperphosphatemia due to end-stage renal disease. The primary endpoint assessed the change in serum phosphate levels from baseline at Week 12. Patients on Repotrectinib experienced an average reduction in serum phosphate of 2.8 mg/dL (from 7.5 mg/dL at baseline to 4.7 mg/dL), indicating an improvement. Patients on sevelamer saw an average reduction of 2.1 mg/dL (from 7.6 mg/dL at baseline to 5.5 mg/dL).
Repotrectinib also led to a higher proportion of patients achieving target phosphate levels (below 5.5 mg/dL) at Week 12, with 72% of patients on Repotrectinib reaching this goal, compared to 58% of patients on sevelamer. Additionally, Repotrectinib resulted in a greater average reduction in calcium-phosphate product (Ca x P) of 25 mg²/dL², compared to an 18 mg²/dL² reduction with sevelamer.
Currently Recruiting Trials
Several clinical trials are actively seeking participants to further explore the potential of Repotrectinib. These studies aim to understand how this investigational drug works in different types of cancer, focusing on its safety and effectiveness. Participating in a clinical trial can offer access to new treatments and contribute to medical knowledge.
One such trial, NCT06315010, known as REPOSE, is a Phase II study. It is investigating Repotrectinib in patients with non-small cell lung cancer (NSCLC) who have active brain metastases and whose tumors have a specific ROS1 gene rearrangement. This trial plans to enroll up to 20 participants.
Another Phase II study, NCT06552234, focuses on the efficacy of Repotrectinib in frail and/or elderly patients with advanced NSCLC that also has a ROS1 rearrangement. This study aims to enroll 30 participants, addressing the need for new treatments when patients develop resistance to existing ROS1 inhibitors.
For patients with advanced or metastatic EGFR mutant NSCLC, a Phase I study, NCT04772235, is exploring Repotrectinib in combination with osimertinib. This trial is designed to determine the safety and optimal dosing of this combination, with an enrollment target of 32 participants.
Repotrectinib is also being studied in pediatric and young adult populations. A Phase I/II study, NCT05004116, is evaluating Repotrectinib in combination with chemotherapy for children and young adults with advanced or metastatic solid tumors. This trial is seeking up to 77 participants to assess safety and find the highest tolerable dose.
Additionally, NCT04094610 is a Phase I/II study for pediatric and young adult subjects with locally advanced or metastatic solid tumors, lymphoma, or primary CNS tumors that harbor ALK, ROS1, or NTRK1-3 alterations. This study aims to enroll 75 participants to evaluate the safety and tolerability of Repotrectinib at different dose levels.
Finally, a large Phase I/II study, NCT03093116, is recruiting up to 500 adult subjects with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. This foundational study is determining the maximum tolerated dose and recommended Phase II dose of Repotrectinib.
Where to Participate
Clinical trials for Repotrectinib are available across a wide geographic area, offering opportunities for participation in many locations. Currently, these studies are being conducted at 64 sites across 45 cities in 23 states.
The cities with the most active recruiting sites include:
- New York, New York (5 sites)
- Boston, Massachusetts (4 sites)
- Houston, Texas (4 sites)
- Aurora, Colorado (3 sites)
- Los Angeles, California (2 sites)
- Philadelphia, Pennsylvania (2 sites)
- Memphis, Tennessee (2 sites)
- Dallas, Texas (2 sites)
- Orlando, Florida (2 sites)
- St Louis, Missouri (2 sites)
Eligibility for these trials generally includes individuals aged 1 to 25 years, with participation open to all genders. It is important to note that these trials are not open to healthy volunteers, as they focus on patients with specific cancer diagnoses.
Development Timeline
The journey of Repotrectinib in clinical development began on March 28, 2017, with its first clinical trial. Since then, a total of 13 trials have been initiated, enrolling over 1,010 participants to date, with the latest trial projected to conclude in November 2025.
Early development saw Repotrectinib primarily investigated in Phase I studies, with 5 trials at this stage, focusing on initial safety and dosing. As more was learned, the program progressed into Phase I/II and Phase II studies, with 3 trials in each of these phases, allowing for a deeper look into the drug's efficacy and continued safety. There is also one Phase III trial underway, indicating advanced development.
Initially, the drug's pipeline explored conditions such as IBS-C and hyperphosphatemia. However, its development quickly expanded to target various solid tumors. Key sponsors like Bristol-Myers Squibb and Turning Point Therapeutics, Inc. have been instrumental in driving this research. The focus broadened to include metastatic and locally advanced solid tumors, lymphoma, and primary CNS tumors. Notably, Repotrectinib's development has significantly expanded into non-small cell lung cancer (NSCLC), including advanced stages, and those with specific ROS1 gene rearrangements or EGFR mutations, addressing critical unmet needs in these patient populations.