Selumetinib + Olaparib for Cancer

Overseen By Shannon Westin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Brain metastases, Cardiac conditions, others

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

Compensation: Varies

Number of Visits: 32

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose pairing of selumetinib (a cancer therapy) and olaparib (also known as Lynparza, a cancer treatment) for advanced or recurrent solid tumors, such as ovarian cancer, particularly when other treatments have failed. The researchers aim to assess whether this combination can effectively manage cancer and evaluate its safety. The trial suits individuals with advanced cancer that hasn't responded to standard treatments or has recurred. Participants will take both medications and undergo close monitoring to evaluate the combination's effectiveness. 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.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for some drugs. If you are taking strong or moderate CYP3A inducers or inhibitors, you will need to stop them for a few weeks before starting the trial. Check with the study team to see if your specific medications are affected.

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

Research has shown that combining selumetinib and olaparib yields promising safety results from earlier studies. Selumetinib, not yet FDA-approved, is well absorbed when taken orally and has demonstrated good safety in numerous studies. Olaparib, already FDA-approved for ovarian cancer with specific genetic changes, has been used safely by many patients.

In studies using both selumetinib and olaparib together, the combination was generally well-tolerated, with most side effects being mild or manageable. This includes patients with solid tumors, where the combination showed benefits, particularly in those with specific genetic mutations. These findings suggest a reasonable safety profile, making the combination a potential option for patients with advanced or recurring cancer. However, as this is a Phase 1 trial, the primary goal is to determine the safest dose for these drugs together, so safety remains under careful study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Selumetinib and Olaparib because they bring a unique combination approach to fighting certain cancers, like endometrial and ovarian cancers, especially in cases with specific genetic markers like RPA. Unlike traditional chemotherapy or standalone PARP inhibitors, this combination targets multiple pathways crucial for cancer cell survival and repair. Olaparib is a PARP inhibitor that blocks a protein used by cancer cells to repair their DNA, while Selumetinib inhibits a different pathway (MEK), potentially enhancing the cancer-fighting effects. This dual action could offer a more effective treatment option by attacking cancer cells on two fronts, making it an exciting development in cancer therapy.

What evidence suggests that the combination of selumetinib and olaparib could be effective for advanced or recurrent solid tumors?

Research has shown that combining selumetinib and olaparib may help treat certain solid tumors. This trial includes treatment arms for specific types of endometrial and ovarian cancers, where early success has been observed. Selumetinib blocks certain proteins and has effectively treated cancers such as lung and melanoma. Olaparib is already approved for ovarian cancer with specific genetic changes. This combination aims to enhance effectiveness by targeting different pathways of cancer growth. ^{1 2 4 6 7}

Who Is on the Research Team?

Shannon Westin, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced or recurrent solid tumors, including various cancers like breast, thyroid, and cervical cancer. Participants must have a life expectancy of at least 16 weeks and be able to follow the study protocol. Women should not be pregnant or breastfeeding and must use effective contraception; men also need to use condoms. Patients should have adequate organ function and may have had any number of prior chemotherapy treatments but must be recovered from major surgeries or previous treatment side effects.

Inclusion Criteria

My side effects from previous treatments are mild, except for hair loss.

I am using two effective birth control methods.

I will use a condom during and for 3 months after treatment if my partner could get pregnant.

Exclusion Criteria

You have a lot of lung disease in both sides of your lungs as shown on a special type of X-ray called HRCT scan.

I haven't had chemotherapy or radiotherapy (except for comfort care) in the last 3 weeks.

I am currently taking certain medications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase 1)

Participants receive increasing doses of selumetinib and olaparib to determine the maximum tolerated dose

28 days

Visits on Days 1, 8, 15, and 22 of Cycle 1

Dose Expansion (Phase 2)

Participants receive the maximum tolerated dose of selumetinib and olaparib to evaluate efficacy

28 days per cycle, ongoing as long as beneficial

Visits on Day 1 of each cycle, with additional visits on Days 8, 15, and 22 of Cycle 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

30-day follow-up visit, then phone calls every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Selumetinib

Trial Overview The trial is testing Selumetinib in combination with Olaparib for treating advanced solid tumors over two phases: finding the highest tolerable dose (Phase 1) and then seeing if that dose can control the cancer (Phase 2). Selumetinib isn't FDA approved yet; it's being researched. Olaparib is approved for ovarian cancer with specific genetic mutations but its combination with Selumetinib is investigational.

How Is the Trial Designed?

Group I: Solid Tumors that Harbor Somatic RPA Experimental Treatment 2 Interventions

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Group II: Selumetinib + Olaparib Experimental Treatment 2 Interventions

Dose Escalation Phase: Participants take both Selumetinib and Olaparib by mouth 2 times each day, about 12 hours apart at the Starting Dose Level. Treatment cycle is 28 days. When maximum tolerated dose reached, Dose Expansion Phase begins.

Group III: Ovarian Cancer-Progression-prior PARP Treatment Experimental Treatment 2 Interventions

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Group IV: Ovarian Cancer with RPA Experimental Treatment 2 Interventions

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

Group V: Endometrial Cancer with RPA Experimental Treatment 2 Interventions

Dose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.

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

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

Niraparib has been approved by the FDA for patients with complete or partial response to first-line platinum-based chemotherapy, regardless of their BRCAm or HRD status, expanding treatment options for more patients.

Olaparib, in combination with bevacizumab, has also received FDA approval for patients with epithelial ovarian cancer, indicating that PARP inhibitors are now beneficial not only for BRCAm and HRD-deficient patients but also for those with HRD-proficient tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. Washington, CR., Moore, KN.[2023]

In a phase I study involving 12 patients with advanced solid tumors, the combination of olaparib and bevacizumab was found to be generally well tolerated, with no dose-limiting toxicities reported.

The most common side effects were mild nausea and fatigue, indicating that the treatment has an acceptable safety profile, making it a candidate for further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Dean, E., Middleton, MR., Pwint, T., et al.[2023]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

The pharmacokinetic (PK) profile of olaparib in Chinese patients with advanced solid tumors is similar to that observed in Western and Japanese populations, confirming that the recommended dose of 300 mg twice daily is appropriate for this group.

When olaparib was combined with paclitaxel, there was a significant decrease in olaparib exposure, and while adverse events were rare, hematological side effects were more common in patients receiving the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours. Yuan, P., Shentu, J., Xu, J., et al.[2020]

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

In a Phase I study involving 28 Japanese patients with advanced solid tumors, olaparib tablets at doses of 200 and 300 mg twice daily were found to be tolerable, with no dose-limiting toxicities reported.

The most common side effects included nausea, decreased appetite, anemia, and constipation, but no confirmed antitumor responses were observed, leading to the selection of 300 mg bid as the recommended dose for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Yonemori, K., Tamura, K., Kodaira, M., et al.[2022]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4469526/

A phase II evaluation of selumetinib (AZD6244, ARRY ... The primary objective of this study was to assess the efficacy and safety of selumetinib in patients with recurrent or persistent endometrial ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25887099/

A phase II evaluation of selumetinib (AZD6244, ARRY-142886 ... We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer. Methods: This was a phase II ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03162627

NCT03162627 | Selumetinib and Olaparib in Solid Tumors This study has 2 phases: Phase 1 (dose escalation) and Phase 2 (dose expansion). The goal of Phase 1 of this clinical research study is to find the highest ...

4. onclive.com onclive.com/view/early-success-with-olaparib-plus-selumetinib-leads-to-further-exploration-in-ras-mutated-gynecologic-cancers

Early Success With Olaparib Plus Selumetinib Leads to ... The degree of clinical benefit observed with olaparib (Lynparza) plus selumetinib (Koselugo) in patients with RAS-mutated endometrial and ovarian cancers has ...

5. researchgate.net researchgate.net/publication/256925385_A_phase_II_evaluation_of_selumetinib_AZD6244_ARRY-142886_a_selective_MEK-12_inhibitor_in_the_treatment_of_recurrent_or_persistent_endometrial_cancer_An_NRG_OncologyGynecologic_Oncology_Group_study

A phase II evaluation of selumetinib (AZD6244, ARRY ... The efficacy of selumetinib in various solid tumors such as colorectal cancer, lung cancer, neurofibroma, and melanoma is investigated. The ...

6. withpower.com withpower.com/trial/phase-2-recurrence-11-2022-3f4aa

Selumetinib + Olaparib for Ovarian and Endometrial Cancer This Phase 2 medical study run by National Cancer Institute (NCI) is evaluating whether Olaparib and Selumetinib Sulfate will have tolerable side effects ...

7. cancernetwork.com cancernetwork.com/view/olaparib-plus-selumetinib-show-benefit-in-ras-mutated-ovarian-and-endometrial-cancers

Olaparib Plus Selumetinib Show Benefit in RAS-Mutated ... Patients with RAS-mutated ovarian or endometrial cancer benefitted most from the recommended phase 2 dose of olaparib (Lynparza) plus selumetinib.