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

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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 tolerable dose combination of selumetinib and olaparib that can be given to patients who have solid tumors that are advanced or recurrent (has returned after treatment). The goal of Phase 2 is to learn if the highest tolerable dose combination found in Phase 1 can help to control advanced or recurrent solid tumors. The safety of the study drug combination will also be studied in both parts. This is an investigational study. Selumetinib is not FDA approved or commercially available. It is currently being used for research purposes only. Olaparib is FDA approved and commercially available for the treatment of ovarian cancer that has a certain type of genetic mutation (change). It is considered investigational to use selumetinib in combination with olaparib to treat advanced or recurrent cancer. The study doctor can explain how the study drugs are designed to work. Up to 90 participants will be enrolled in this study. All will take part at MD Anderson.

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 the combination of Selumetinib and Olaparib safe for humans?

Olaparib (also known as Lynparza) has been tested in various studies and is generally considered safe for humans, with research showing its safety in patients with advanced solid tumors. However, specific safety data for the combination of Selumetinib and Olaparib is not provided in the available research. ^{1 2 3 4 5}

What makes the drug combination of Selumetinib and Olaparib unique for cancer treatment?

The combination of Selumetinib and Olaparib is unique because it targets cancer through two different mechanisms: Selumetinib inhibits MEK1/2, a protein involved in cell growth, while Olaparib inhibits PARP, a protein involved in DNA repair. This dual approach may offer a novel way to treat cancers that are resistant to other therapies. ^{2 3 6 7 8}

What data supports the effectiveness of the drug Olaparib in cancer treatment?

Olaparib has shown promising activity in treating ovarian cancer, especially in patients with BRCA mutations, and has been effective in combination with other drugs like cediranib to improve progression-free survival in certain cases. ^{2 3 9 10 11}

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

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 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]

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]

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]

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]

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 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]

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]

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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. [2023]

2. England 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]

4. United States 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. [2022]

5. England pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

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

7. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. [2022]

8. Germany 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. [2020]

9. United States 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. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. [2019]

11. New Zealand pubmed.ncbi.nlm.nih.gov

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