Uprosertib + Dabrafenib + Trametinib for Advanced Skin Cancer

No longer recruiting at 16 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP2C8 inducers

Disqualifiers: Cardiac arrhythmias, Diabetes, Hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 5

Duration: Up to 56 days for dose escalation, then 28-day cycles

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose and assess the side effects of a new treatment combination for advanced skin cancer. It tests uprosertib (an experimental treatment) with dabrafenib and trametinib to evaluate their effectiveness in stopping cancer cell growth. The trial targets individuals with stage IIIC-IV melanoma who have a specific genetic mutation called BRAF^V600 and have not responded to other treatments. Participants should have cancer that has spread and cannot be surgically removed. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take medications that strongly affect certain liver enzymes or use herbal remedies like St. John's wort. It's best to discuss your current medications with the trial team.

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

Research has shown that the combination of dabrafenib and trametinib can help some patients with a certain type of skin cancer live longer, and most people tolerate these drugs well. However, when uprosertib was added, past studies found that 59% of patients experienced noticeable side effects, and 6% had very serious ones, indicating that uprosertib might be harder for some patients to tolerate.

In these early studies, researchers continue to test the combination of all three drugs to determine the right dose and ensure safety. As the study is in an early phase, researchers are still learning about how these drugs work together and their effects on patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of uprosertib, dabrafenib, and trametinib for advanced skin cancer because it targets the cancer cells in a unique way. While standard treatments often focus on blocking a single pathway, this combination targets multiple pathways involved in cancer cell growth and survival. Uprosertib is a new addition that inhibits a protein called AKT, which is crucial for cancer cell metabolism and survival, potentially enhancing the effectiveness of dabrafenib and trametinib. This multi-targeted approach holds the promise of being more effective in halting disease progression compared to existing treatments.

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

Studies have shown that using dabrafenib and trametinib together can slow advanced skin cancer, with about 19% of patients experiencing no cancer progression after five years. In this trial, participants will receive a combination of uprosertib, dabrafenib, and trametinib. Adding uprosertib to these drugs might enhance their effectiveness by blocking enzymes that help cancer grow. Research indicates that trametinib increases dabrafenib levels in the body, potentially making the treatment more effective. This combination targets several pathways of cancer cell growth, potentially offering a stronger treatment option. ^{2 3 6 7 8}

Who Is on the Research Team?

Antoni Ribas

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for adults with stage IIIC-IV cancer, specifically those with BRAF^V600 mutant metastatic cancer. Participants must have resolved any previous treatment side effects to a mild level and be able to take oral medication without significant gastrointestinal issues. They should not be pregnant or nursing, have active hepatitis B/C, uncontrolled illnesses like heart disease or diabetes, or a history of severe allergic reactions to similar drugs.

Inclusion Criteria

Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

I can provide tissue from when my disease worsened after BRAF inhibitor therapy or allow a new biopsy.

Patients must have specific results for their lab tests.

Exclusion Criteria

Patients must not be pregnant or nursing

I don't have any serious ongoing illnesses, recent major surgery, or history of severe lung disease.

I do not have a history or current signs of retinal vein occlusion.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive dabrafenib, trametinib, and uprosertib in cycles of 28 days, with dose escalation to determine the maximum-tolerated dose

Up to 56 days for dose escalation, then 28-day cycles

Every 2 weeks during days 1-56, then every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 3 months for 1 year, then every 6 months for 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Dabrafenib
• Trametinib
• Uprosertib

Trial Overview

The trial is testing the combination of uprosertib with dabrafenib and trametinib in patients with advanced cancer stages. It aims to find the best dose that can block enzymes needed for tumor cell growth and determine how effective this drug combo is compared to current treatments.

How Is the Trial Designed?

Group I: Treatment (uprosertib, dabrafenib, trametinib) Experimental Treatment 7 Interventions

Dabrafenib mesylate and uprosertib (Phase I): Patients receive dabrafenib PO BID and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial. Dabrafenib mesylate, trametinib dimethyl sulfoxide, and uprosertib (Phase I and Phase II): Patients receive dabrafenib PO BID, trametinib PO QD, and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.

Dabrafenib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in United States as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600E mutation
• Adjuvant treatment of melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in Canada as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in Japan as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/31166680/

Five-Year Outcomes with Dabrafenib plus Trametinib in ...

The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years.

2.

withpower.com

withpower.com/trial/phase-2-neoplasms-6-2013-6c1df

Uprosertib + Dabrafenib + Trametinib for Advanced Skin ...

Uprosertib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving uprosertib with ...

3.

acsjournals.onlinelibrary.wiley.com

acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35200

A phase 1 study of triple‐targeted therapy with BRAF, MEK ...

Although previous data suggest that the addition of trametinib caused a 23% increase in dabrafenib exposure and a 33% increase in the desmethyl ...

4.

aging.networkofcare.org

aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT01902173?keyword=%22Stage%20IIIC%20Cutaneous%20Melanoma%22

Uprosertib, Dabrafenib, and Trametinib in Treating Patients ...

To evaluate the objective response rate (confirmed and unconfirmed, complete and partial responses) in patients with BRAF\^V600 mutant metastatic melanoma who ...

5.

trial.medpath.com

trial.medpath.com/clinical-trial/abca524fe6a6a405/nct01902173-safety-efficacy-akt-inhibitor-gsk2141795-combination-dabrafenib-trametinib-braf-mutant

Uprosertib, Dabrafenib, and Trametinib in Treating Patients ...

Uprosertib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving uprosertib with ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5834102/

long-term survival and safety analysis of a phase 3 study

These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and ...

7.

researchgate.net

researchgate.net/publication/345632508_COMBI-d_A_randomized_double-blinded_Phase_III_study_comparing_the_combination_of_dabrafenib_and_trametinib_to_dabrafenib_and_trametinib_placebo_as_first-line_therapy_in_patients_pts_with_unresectable_

COMBI-d: A randomized, double-blinded, Phase III study ...

... Among BRAF inhibitors, median overall survival ranged from 9.2 months (for vemurafenib) [28] to 18.3 months (for dabrafenib + trametinib) [ ...

8.

escholarship.org

escholarship.org/uc/item/6c2779pg

Phase I dose-escalation trial of the oral AKT inhibitor ...

Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib ...