Avapritinib for Solid Tumors

Overseen By Jordi R Rodon, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A4 inhibitors, Strong CYP3A4 inducers

Disqualifiers: GIST, TKI-resistant CKIT mutations, 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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 36

Duration: Up to 50 months

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called avapritinib to determine if it can stop the growth of certain solid tumors with a specific genetic mutation. These tumors are advanced or have metastasized. The trial seeks patients with these tumors who have not benefitted from or have declined standard treatments. Those diagnosed with a solid tumor such as melanoma, breast, or lung cancer and have a known CKIT or PDGFRA mutation might find this trial suitable. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of 2 weeks or 5 times the half-life of any strong CYP3A4 inhibitors or inducers before starting the study treatment. If you are taking such medications, you will need to stop them before participating.

Is there any evidence suggesting that avapritinib is likely to be safe for humans?

Research has shown that avapritinib is generally well-tolerated by patients. In one study, only 3% of participants stopped taking it due to side effects, indicating that most people can use avapritinib without major issues. While some side effects might occur, they usually aren't serious enough to require stopping treatment. Avapritinib has proven safe for treating certain tumors, such as gastrointestinal stromal tumors, which share genetic traits with the tumors in this trial. This existing safety record offers reassurance about its use for treating solid tumors with specific mutations. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about avapritinib because it targets specific mutations in tumors, offering a more personalized treatment approach. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, avapritinib specifically inhibits the KIT and PDGFRA proteins often mutated in solid tumors. This targeted mechanism not only promises increased effectiveness but also potentially reduces the side effects typically associated with less specific cancer treatments.

What evidence suggests that avapritinib might be an effective treatment for malignant solid tumors?

Research has shown that avapritinib, the treatment under study in this trial, effectively treats certain tumors. Studies have found it works well for tumors with specific genetic changes, such as those in the CKIT or PDGFRA genes. Avapritinib is particularly effective for gastrointestinal stromal tumors (GIST) with the PDGFRA mutation. This treatment blocks enzymes that promote tumor cell growth, helping to control tumor growth. Patients have experienced improved quality of life and lasting benefits from avapritinib. Overall, avapritinib appears promising for managing malignant solid tumors with these genetic mutations. ^{1 2 4 5 6}

Who Is on the Research Team?

Jordi Rodon Ahnert

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced or metastatic solid tumors harboring specific genetic mutations (CKIT or PDGFRA) may join this trial. They should have tried standard treatments without success, be able to follow the study protocol, and agree to use effective contraception. Those with certain heart conditions, unstable brain metastases, severe bleeding history, or on strong CYP3A4 inhibitors/inducers are excluded.

Inclusion Criteria

I am a woman who cannot become pregnant due to age, surgery, or confirmed by a test.

I am using or will use effective birth control during and up to 6 weeks after the study.

The patient (or legally acceptable representative if applicable) provides written informed consent for the study

Exclusion Criteria

History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the investigator

I haven't had any blood clot events in the past 6 months.

I haven't had cancer treatment or major surgery in the last 2 weeks and have recovered from side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avapritinib orally once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 50 months

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 8 weeks.

Up to 4 years

Follow-up visits every 8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Avapritinib

Trial Overview The trial is testing avapritinib's effectiveness in stopping tumor growth by inhibiting enzymes needed for cell growth in patients with CKIT/PDGFRA mutation-positive malignant solid tumors that are locally advanced or have spread elsewhere.

How Is the Trial Designed?

Group I: Treatment (avapritinib) Experimental Treatment 1 Intervention

Patients receive avapritinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Avapritinib is already approved in United States, European Union for the following indications:

Approved in United States as Ayvakit for:

• Unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations
• Advanced systemic mastocytosis
• Indolent systemic mastocytosis

Approved in European Union as Ayvakit for:

• Unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations
• Advanced systemic mastocytosis
• Indolent systemic mastocytosis

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Pazopanib, an oral tyrosine kinase inhibitor approved for renal cell carcinoma and soft tissue sarcoma, was primarily excreted unchanged in feces, indicating that it is mainly eliminated through the digestive system rather than the kidneys, with 82.2% of the dose found in feces.

The study found that the absolute oral bioavailability of pazopanib tablets ranged from 14% to 39%, suggesting that while pazopanib is effective, its absorption can vary significantly among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. Deng, Y., Sychterz, C., Suttle, AB., et al.[2021]

Pazopanib is a potent pan-VEGF inhibitor that has shown clinical efficacy in treating metastatic renal cell carcinoma, leading to its recent FDA approval.

In a Phase III clinical trial, pazopanib demonstrated similar effectiveness to other approved treatments but exhibited different toxicity profiles, which may help differentiate it from other VEGFR inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib: therapeutic developments. Limvorasak, S., Posadas, EM.[2021]

Pazopanib, a multikinase inhibitor, was approved by the US FDA in October 2009 for treating advanced renal cell carcinoma, highlighting its significance in cancer therapy.

The drug targets vascular endothelial growth factor receptors, which play a crucial role in tumor growth and blood vessel formation, making it an effective option for managing this type of kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib. Bukowski, RM., Yasothan, U., Kirkpatrick, P.[2021]

Pazopanib is an FDA-approved multi-kinase inhibitor effective in treating advanced renal cell carcinoma (RCC), showing significant clinical activity in metastatic cases.

The drug not only targets VEGF receptors but also affects other receptors, which contributes to its side-effect profile, indicating a broader mechanism of action beyond just inhibiting VEGF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib and anti-VEGF therapy. Drabkin, HA.[2021]

Pazopanib is a multikinase inhibitor that effectively targets key receptors involved in tumor growth and has shown significant efficacy in treating advanced or metastatic soft-tissue sarcoma, as demonstrated in both phase II and randomized phase III studies.

The safety profile of pazopanib is comparable to other tyrosine kinase inhibitors like sunitinib and sorafenib, making it a well-tolerated option for patients with metastatic renal cell carcinoma and soft-tissue sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib for the treatment of soft-tissue sarcoma. Heudel, P., Cassier, P., Derbel, O., et al.[2022]

In a phase I study involving 17 patients, the combination of sorafenib and vorinostat was found to be poorly tolerated in patients with advanced renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), leading to dose reductions and interruptions due to side effects like hand-foot syndrome.

While no confirmed responses were observed, some patients with RCC experienced minor responses, suggesting that lower doses may be necessary for better tolerability and potential efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer. Dasari, A., Gore, L., Messersmith, WA., et al.[2021]

Vorolanib, a novel tyrosine kinase inhibitor, was found to have an acceptable safety profile with no dose-limiting toxicities during a dose escalation study involving 19 patients, and the recommended phase II dose was established at 200 mg once daily.

In terms of efficacy, patients receiving 200 mg of vorolanib showed a 22.2% objective response rate and a median progression-free survival of 9.9 months, indicating promising clinical benefits for those with advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorolanib, an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors: An open-label, phase I dose escalation and dose expansion trial. Song, Y., Wang, J., Ren, X., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02508532

NCT02508532 | (NAVIGATOR) Study of BLU-285 in ... This is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and ...

2. prnewswire.com prnewswire.com/news-releases/blueprint-medicines-announces-data-reinforcing-sustained-clinical-efficacy-and-well-tolerated-safety-profile-of-long-term-ayvakitayvakyt-avapritinib-treatment-at-2025-eha-and-eaaci-congresses-302480690.html

Blueprint Medicines Announces Data Reinforcing ... In newly reported data, AYVAKIT showed sustained clinical benefits across quality-of-life measures that reflect general health status and are ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12065942/

Evaluation of the effectiveness and safety of avapritinib ... This study underscores the effectiveness of avapritinib in treating patients with gastrointestinal stromal tumors (GIST) harboring the PDGFRA ...

4. blueprintmedicines.com blueprintmedicines.com/wp-content/uploads/2024/02/Blueprint-Medicines-Press-Release-AAAAI-2024-February-23-2024.pdf

Blueprint Medicines Highlights AYVAKIT® (avapritinib) ... In multiple in vivo studies, BLU-808 treatment led to dose-dependent inhibition and depletion of mast cells. In addition, BLU-808 improved lung ...

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/32/NCT02508532/SAP_001.pdf

Statistical Analysis Plan Patients with an advanced solid tumor other than GIST must have R/R disease without an available effective therapy. A standard 3+3 DE design using cohorts ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2023/212608Orig1s013.pdf

CENTER FOR DRUG EVALUATION AND RESEARCH Overall, the safety profile of avapritinib in Study BLU-285-2203 Part 2, appears to be similar to that in the safety profile of avapritinib ...