Tovorafenib + Pimasertib for Cancer

Recruiting at 21 trial locations

Overseen By Day One Biopharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Day One Biopharmaceuticals, Inc.

Must not be taking: RAS-RAF-MEK-ERK inhibitors

Disqualifiers: Activating mutation, CSR, RVO, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 48 months

168 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing Tovorafenib, a drug that blocks proteins needed for cancer cell growth, in patients aged 12+ with hard-to-treat melanoma or other solid tumors.

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, if you have previously taken RAS- RAF-, MEK-, or ERK-directed inhibitor therapy, you may not be eligible for Substudy A.

What data supports the effectiveness of the drug Tovorafenib + Pimasertib for cancer?

Research shows that Pimasertib, a part of this drug combination, has been studied for its safety and effectiveness in treating advanced solid tumors and metastatic melanoma, indicating potential benefits in cancer treatment. ^{1 2 3 4 5}

What makes the drug Tovorafenib + Pimasertib unique for cancer treatment?

Tovorafenib (DAY101) combined with Pimasertib is unique because it targets specific pathways involved in cancer cell growth, potentially offering a novel approach for patients who may not respond to standard treatments. This combination may provide a new option for targeting cancer cells more effectively. ^{6 7 8 9 10}

Eligibility Criteria

This trial is for people aged 12 and older with certain types of cancer, like melanoma or colorectal cancer, that have specific genetic changes in the MAPK pathway. They must have measurable disease progression and provide a tissue sample. It's not for those who've had prior treatment targeting the RAS-RAF-MEK-ERK pathway or have certain eye conditions.

Inclusion Criteria

I have signed the consent form and am 18 or older, or I am 12-17 and have given my assent.

My cancer diagnosis is confirmed and has a BRAF or CRAF/RAF1 change.

I can provide recent or new tumor tissue samples for study.

Exclusion Criteria

I have or had eye conditions like CSR or RVO.

I have never been treated with RAS, RAF, MEK, or ERK inhibitors.

My cancer has a known activating mutation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Tovorafenib is evaluated alone or in combination with other therapies to assess safety and efficacy

Up to 48 months

Safety Follow-up

Participants are monitored for safety after treatment

Up to 48 months

Long-term Follow-up

Survival status and subsequent anticancer therapies are collected

Long-term

Treatment Details

Interventions

• DAY101
• Pimasertib Hydrochloride

Trial Overview The study tests Tovorafenib alone or combined with Pimasertib on patients with solid tumors having alterations in the MAPK pathway. This includes different substudies focusing on various genetic mutations related to this pathway.

Participant Groups

Group I: Arm #2 Experimental Treatment 2 Interventions

Tovorafenib plus pimasertib

Group II: Arm #1 (Closed to Enrollment) Experimental Treatment 1 Intervention

Tovorafenib monotherapy

DAY101 is already approved in United States for the following indications:

Approved in United States as Ojemda for:

• Pediatric low-grade glioma with BRAF gene mutations

Who Is Running the Clinical Trial?

Day One Biopharmaceuticals, Inc.

Lead Sponsor

Trials

8

Recruited

1,100+

Findings from Research

In a phase Ib study involving 146 patients with advanced solid tumors, the combination of pimasertib (a MEK1/2 inhibitor) and voxtalisib (a pan-PI3K and mTORC1/mTORC2 inhibitor) was found to have a maximum-tolerated dose of 90 mg and 70 mg respectively, with a recommended phase 2 dose of 60 mg for pimasertib.

Despite some initial responses, including one complete response and five partial responses, the treatment showed poor long-term tolerability, with 73% of patients requiring dose interruptions and 26% discontinuing due to treatment-emergent adverse events like diarrhea and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. Schram, AM., Gandhi, L., Mita, MM., et al.[2021]

In the FLAURA China study involving 136 patients with EGFR mutation-positive advanced non-small-cell lung cancer, first-line treatment with osimertinib significantly improved progression-free survival (PFS) by 8 months compared to comparator EGFR TKIs, with median PFS of 17.8 months versus 9.8 months.

Osimertinib also showed a trend towards improved overall survival (OS) with a median of 33.1 months compared to 25.7 months for the comparator group, while the safety profile was consistent with previous findings, with no new safety signals identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Cheng, Y., He, Y., Li, W., et al.[2022]

The combination of osimertinib with selumetinib or savolitinib showed a promising objective response rate of around 42-44% in patients with advanced EGFR-mutant non-small-cell lung cancer, indicating potential efficacy of these combinations.

However, combining osimertinib with durvalumab was not feasible due to a higher incidence of interstitial lung disease, highlighting safety concerns with this particular combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Oxnard, GR., Yang, JC., Yu, H., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours. [2023]

2. England pubmed.ncbi.nlm.nih.gov

A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Phase I single dose, two-period and two-sequence cross-over trial to evaluate the relative bioavailability of two oral pimasertib formulations in advanced cancer patients. [2018]

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

Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients. [2021]

5. France pubmed.ncbi.nlm.nih.gov

Selective Oral MEK1/2 Inhibitor Pimasertib in Metastatic Melanoma: Antitumor Activity in a Phase I, Dose-Escalation Trial. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

The inhibition of the pemetrexed-activated MAPK pathway via sorafenib is involved in the synergistic mechanism of sorafenib subsequent potentiation of pemetrexed cytotoxicity in EGFR TKI-resistant cell lines. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of Osimertinib in Combination With Chemotherapy and Bevacizumab for Untreated Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer: Case Report. [2021]

8. France pubmed.ncbi.nlm.nih.gov

Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. [2022]

9. England pubmed.ncbi.nlm.nih.gov

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. [2022]

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

Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status. [2022]