Alisertib + Osimertinib for Lung Cancer

Overseen By Lisa Tan

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Collin Blakely

Must be taking: Osimertinib

Must not be taking: QTcF prolonging, CYP3A4 inducers

Disqualifiers: Radiation, Transplant, GI disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

38 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and optimal dose of alisertib combined with osimertinib for treating stage IV lung cancer with a specific EGFR mutation. Alisertib may inhibit cancer growth by blocking a protein that promotes tumor growth, while osimertinib targets a specific mutant protein in cancer cells. The trial is for individuals with stage IV EGFR-mutated lung cancer who are currently taking osimertinib and have experienced some success with it. Participants should have been on osimertinib for at least three months and no more than six months, without major side effects. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be currently receiving and tolerating osimertinib 80 mg daily. Some medications, like proton pump inhibitors, are restricted, and you should discuss your specific medications with the trial team.

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

Research has shown that combining alisertib and osimertinib is generally safe. Previous studies found that patients with EGFR-mutated lung cancer tolerated this combination well. Most side effects were mild and similar to those seen with osimertinib alone, indicating that adding alisertib does not significantly increase risk. Overall, the research suggests that this treatment combination is manageable for patients, though individual experiences may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of alisertib and osimertinib for treating EGFR-mutant non-small cell lung cancer (NSCLC) because it offers a novel approach to combatting cancer. Unlike other treatments that focus solely on the EGFR pathway, alisertib targets the Aurora A kinase, which plays a key role in cell division and tumor growth. This dual approach has the potential to enhance the effectiveness of osimertinib, a standard EGFR inhibitor, especially in patients who have shown only partial responses or stable disease. By addressing multiple pathways, this combination could potentially delay disease progression and overcome resistance seen with current treatments.

What evidence suggests that this trial's treatments could be effective for EGFR-mutated lung cancer?

Studies have shown that osimertinib effectively treats EGFR-mutant non-small cell lung cancer (NSCLC). One study found that patients taking osimertinib lived an average of 38.6 months, longer than those on other treatments. In this trial, some participants will continue receiving osimertinib, while others will receive a combination of osimertinib and alisertib. Alisertib blocks a protein called Aurora Kinase A, which aids cancer cell growth. Early research suggests that combining alisertib with osimertinib is safe for patients and might help stop tumor growth. These findings offer hope for improved lung cancer treatment outcomes. ^{1 2 6 7 8}

Who Is on the Research Team?

Collin Blakely, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults with stage IV lung cancer characterized by specific EGFR mutations, who are currently taking and tolerating osimertinib. They must have good performance status, measurable disease, acceptable lab values, agree to provide samples for research, use contraception if applicable, and not be pregnant or breastfeeding. Excluded are those with certain brain metastases, extensive prior radiation therapy, severe medical conditions or those on conflicting medications.

Inclusion Criteria

I am fully active or can carry out light work.

Additional criteria for Cohort A and Cohort B.

Voluntary written consent before performance of any study-related procedure not part of standard of care.

Exclusion Criteria

I am not on medication that interferes with the study drugs.

I do not have any stomach or intestine problems that could affect how a medicine is absorbed.

My cancer has spread to the lining of my brain and spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive alisertib orally twice daily on days 1-3, 8-10, and 15-17, and osimertinib once daily on days 1-28 in 28-day cycles

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 3 to 6 months for up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Alisertib
• Osimertinib

Trial Overview This trial is testing the combination of two drugs: Alisertib (which blocks a protein that may help lung cancer grow) and Osimertinib (which targets mutant proteins to reduce tumor growth). The study aims to determine the safest dose of Alisertib when used with Osimertinib and observe their effects on advanced-stage lung cancer.

How Is the Trial Designed?

Group I: Dose Expansion: Cohort C Experimental Treatment 2 Interventions

Stage IV EGFR-mutant NSCLC patients with no known tumor non-synonymous TP53 genomic alteration who are currently receiving first line osimertinib treatment and have received at least 3 months, but no more than 6 months, of osimertinib with a best response of PR or SD. Patients may receive alisertib therapy until lack of clinical benefit or intolerable toxicity.

Group II: Dose Expansion: Cohort B Experimental Treatment 2 Interventions

Stage IV EGFR-mutant NSCLC patients who are currently receiving first line osimertinib treatment and have received at least 3 months, but no more than 6 months, of osimertinib with a best response of PR or SD. Patients may receive alisertib therapy until lack of clinical benefit or intolerable toxicity.

Group III: Dose Expansion: Cohort A Experimental Treatment 2 Interventions

Stage IV EGFR-mutant NSCLC currently receiving and progressing on osimertinib who have received no more than one additional line of systemic cancer therapy other than osimertinib (e.g., chemotherapy +/- immunotherapy, amivantamab +/- Lazertinib) for metastatic disease. Patients may receive alisertib therapy until lack of clinical benefit or intolerable toxicity.

Group IV: Dose Escalation (Closed to Enrollment) Experimental Treatment 2 Interventions

Patients will continue to receive osimertinib 80 mg PO daily as part of standard of care therapy during screening and study treatments. Alisertib will be administered to eligible patients in combination with osimertinib at doses ranging from 20 mg to 50 mg PO twice daily on days 1-3, 8-10, and 15-17 of a 28-day cycle. The starting alisertib dose will be 30 mg twice daily (dose level 1). All patients at a given dose level must complete the DLT period before any additional cohorts can be opened.

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

Approved in United States as Alisertib for:

• Acute myeloid leukemia (AML)

Approved in European Union as Alisertib for:

• None approved; under investigation for various cancers

Who Is Running the Clinical Trial?

Collin Blakely

Lead Sponsor

Trials

2

Recruited

40+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Published Research Related to This Trial

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]

In a study of 240 advanced non-small-cell lung cancer (NSCLC) patients with acquired resistance to EGFR TKIs, 52.9% had the T790M mutation after rebiopsy, highlighting the mutation's prevalence in treatment resistance.

Patients with the T790M mutation who had previously used osimertinib experienced significantly longer post-progression survival (42.6 months) compared to those without osimertinib (18.0 months) or without the mutation (18.8 months), suggesting osimertinib's effectiveness as a standard treatment for T790M-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. Chiang, CL., Huang, HC., Shen, CI., et al.[2022]

Osimertinib, an irreversible tyrosine kinase inhibitor, showed excellent activity in treating a 69-year-old man with metastatic EGFR-mutated non-small cell lung cancer, leading to a rapid treatment response despite initial severe pancytopenia.

After experiencing pancytopenia, the patient's dose of osimertinib was reduced from 80 mg to 40 mg daily, which allowed for continued effective treatment without further adverse events, demonstrating the potential for safe dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. Di Marino, P., Chiapperino, C., Primavera, FC., et al.[2022]

Osimertinib (TAGRISSO) received accelerated FDA approval for treating metastatic non-small cell lung cancer with the EGFR T790M mutation, showing significant tumor response rates of 57% and 61% in two major trials involving 411 patients.

While osimertinib demonstrated promising efficacy, common side effects included diarrhea (42%) and rash (41%), with 28% of patients experiencing severe adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Khozin, S., Weinstock, C., Blumenthal, GM., et al.[2022]

Osimertinib (AZD9291) is effective in prolonging survival for non-small cell lung cancer patients with EGFR mutations, but resistance to the drug is a common issue, prompting the need to explore resistance mechanisms.

In this study, AZD9291-resistant NSCLC cell lines were established, revealing significant changes in circular RNA (circRNA) expression profiles, which may contribute to drug resistance and could serve as potential targets for future gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. Chen, T., Luo, J., Gu, Y., et al.[2022]

In a retrospective analysis of 32 patients with EGFR T790M-mutant non-small-cell lung cancer, osimertinib showed a 50% objective response rate and a median progression-free survival of 11.3 months, indicating its efficacy in clinical practice.

The median overall survival was 18.3 months, with better outcomes observed in patients without cerebral metastases and those with better performance status, highlighting the importance of these factors in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. Knetki-Wróblewska, M., Kowalski, DM., Czyżewicz, G., et al.[2022]

In a study of 46 treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer, alternating therapy with osimertinib and afatinib resulted in a median progression-free survival of 21.3 months, indicating promising efficacy despite not meeting the primary endpoint of 12-month progression-free survival probability.

The treatment was generally well-tolerated, with common side effects including diarrhea (73.9%) and rash (63.0%), and only a few cases of serious pneumonitis, suggesting a manageable safety profile for this alternating therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). Hayashi, H., Yonesaka, K., Nakamura, A., et al.[2022]

In a study of 94 patients with advanced non-small-cell lung cancer (NSCLC) who had previously been treated, osimertinib showed a 47.3% overall objective response rate and a 90.1% disease control rate, indicating its effectiveness in this population.

Patients with the T790M mutation experienced significantly longer progression-free survival (PFS) compared to those without the mutation, highlighting osimertinib's targeted efficacy, especially in those with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. Mu, Y., Xing, P., Hao, X., et al.[2022]

Osimertinib (Tagrisso) is a targeted therapy approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have the EGFR T790M mutation and have progressed after previous treatments.

The drug received special designations from the FDA, including breakthrough therapy and priority review, highlighting its significance in treating resistant forms of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Skoulidis, F., Papadimitrakopoulou, VA.[2022]

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