Tovorafenib + Pimasertib for Cancer

No longer recruiting at 25 trial locations

Overseen By Day One Biopharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 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)

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 48 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called tovorafenib (also known as DAY101), targeting melanoma or other solid tumors with specific genetic changes in the BRAF or CRAF/RAF1 genes. The researchers aim to assess the treatment's effectiveness and safety for those whose cancer has returned or worsened. The trial includes two groups: one for melanoma and another for any solid tumor with the specified genetic changes. Suitable participants have been diagnosed with melanoma or a solid tumor, possess the specific genetic changes, and show signs of cancer recurrence or progression. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that tovorafenib (also called OJEMDA) has undergone safety testing in people with certain cancers. Earlier studies found tovorafenib safe enough for use. For example, one study discovered that the recommended dosing schedule was manageable for patients. Additionally, the FDA has approved tovorafenib for treating some types of cancer, indicating some evidence of its safety. However, like any treatment, it may cause side effects, which can vary among individuals. Discuss any concerns with the trial team or your doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard care options for cancer, which often include chemotherapy and immunotherapy, Tovorafenib offers a unique approach. Researchers are excited about Tovorafenib because it specifically targets a pathway known as the MAPK pathway, which is often overactive in certain cancers like melanoma. This precision targeting may lead to more effective treatment outcomes with potentially fewer side effects. Additionally, Tovorafenib is used as a monotherapy, which simplifies the treatment regimen compared to combination therapies, making it a promising new option for patients.

What evidence suggests that this trial's treatments could be effective for cancer?

Research has shown that tovorafenib, which participants in this trial may receive as monotherapy, yields promising results for treating certain cancers with specific genetic traits. In studies, 46% of children with cancer experienced tumor shrinkage after three months of treatment with tovorafenib, indicating the drug's effectiveness in reducing tumor size. Additionally, early reports from patients with BRAF fusion melanoma, a type of skin cancer, have shown positive results. These findings strongly suggest that tovorafenib could effectively treat melanoma and other solid tumors with BRAF or RAF1 fusions. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

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

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

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

My brain metastases have been treated and are stable.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Tissue Agnostic Cohort Experimental Treatment 1 Intervention

Tovorafenib monotherapy

Group II: Melanoma Cohort 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+

Published Research Related to This Trial

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]

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]

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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04985604

Study Details | NCT04985604 | Tovorafenib (DAY101) ...

This is a Phase 2, multi-center, open-label to evaluate the efficacy and safety of tovorafenib (DAY101) in participants ≥12 years of age with recurrent or ...

2.

dayonebio.com

dayonebio.com/wp-content/uploads/ClinicalactivityofthetypeIIpan-RAFinhibitortovorafenibinBRAF-fusionmelanoma.pdf

Clinical activity of the type II pan-RAF inhibitor tovorafenib in ...

• Preliminary clinical activity of tovorafenib monotherapy in the first 3 patients with. BRAF fusion melanoma is reported (data cutoff Feb 8, 2023; Table 1).

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10261210/

Phase 1 study of the pan-RAF inhibitor tovorafenib in patients ...

Overall, there were 13 on-study deaths (12 fatal SAEs, and 1 patient who died of gastric cancer not reported as an SAE) with only one, ...

4.

fda.gov

fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-ojemda

Drug Trials Snapshots: OJEMDA

The major efficacy outcome measure was ORR defined as the proportion of patients with complete response, partial response, or minor response by ...

5.

ojemda.com

ojemda.com/results-with-ojemda/tumor-response-with-ojemda

Clinical study results | OJEMDA™ (tovorafenib)

ON SCREEN: 46% of children (18 out of 39) saw tumor shrinkage at 3 months after their first MRI scan* *These data were collected during the clinical study, and ...

6.

ir.dayonebio.com

ir.dayonebio.com/news-releases/news-release-details/day-ones-ojemdatm-tovorafenib-receives-us-fda-accelerated

Day One's OJEMDA™ (tovorafenib) Receives US FDA ...

The accelerated approval of OJEMDA is based on data from the Company's pivotal open-label Phase 2 FIREFLY-1 trial, which enrolled a total of 137 ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37219686/

Phase 1 study of the pan-RAF inhibitor tovorafenib in ...

Conclusions: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies.