mTOR/AKT Inhibitors for Endometrial and Ovarian Cancer

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Insulin, Oral hypoglycemics

Disqualifiers: Carcinosarcoma, Brain metastases, Myelodysplastic syndrome, Uncontrolled diabetes, others

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

Compensation: Varies

Number of Visits: 1

Duration: 28 days per cycle

159 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase Ib/II trial studies the side effects and best dose of olaparib and vistusertib (AZD2014) or olaparib and capivasertib (AZD5363) when given together in treating patients with endometrial, triple negative breast cancer, ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent). Olaparib, vistusertib, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications and substances are prohibited within specific wash-out periods, so it's best to discuss your current medications with the trial team.

Is olaparib safe for humans?

Olaparib has been studied in patients with advanced ovarian cancer, and while it offers benefits, it can also cause side effects. Common side effects include blood-related issues and other non-blood-related problems, but the specific details on safety are not fully detailed in the available studies. ^{1 2 3 4 5}

What makes the drug AZD2014, AZD5363, and Olaparib unique for endometrial and ovarian cancer?

This drug combination targets the PI3K/AKT/mTOR pathway, which is often overactive in endometrial and ovarian cancers, offering a novel approach by potentially reducing tumor growth and resistance to other treatments. Unlike standard therapies, this combination includes mTOR inhibitors and Olaparib, a PARP inhibitor, which may enhance effectiveness in these cancers. ^{6 7 8 9 10}

What data supports the effectiveness of the drug AZD2014, AZD5363, Olaparib, Lynparza for endometrial and ovarian cancer?

Research shows that the mTOR/AKT pathway, which these drugs target, is often overactive in endometrial and ovarian cancers. Early studies have shown promising results with mTOR inhibitors in these cancers, suggesting they may help slow tumor growth and improve outcomes. ^{6 8 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?

This trial is for patients with recurrent endometrial, ovarian, peritoneal, fallopian tube cancer or triple negative breast cancer. Participants must have a life expectancy over 4 months and be able to take oral meds. They should agree to use contraception and have specific blood levels within normal ranges. Those with other recent cancers or certain health conditions can't join.

Inclusion Criteria

You are expected to live for more than 4 months.

Understanding and willingness to sign an informed consent

You need to provide samples from when you were first diagnosed or when the cancer came back.

Exclusion Criteria

I am not taking any experimental drugs or additional cancer treatments.

Known hypersensitivity to study drugs or similar drugs

Unsuitability and non-compliance with study procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib and either vistusertib or capivasertib in various dosing schedules over 28-day cycles

28 days per cycle

Continuous monitoring with regular visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are monitored for progression-free survival and response duration

6 months

What Are the Treatments Tested in This Trial?

Interventions

• AZD2014
• AZD5363
• Olaparib

Trial Overview The study tests the combination of olaparib with either vistusertib (AZD2014) or capivasertib (AZD5363) on tumor growth in selected cancers. It aims to find the safest doses and observe how well these drug combinations work against recurrent cancers by blocking enzymes that promote cell growth.

How Is the Trial Designed?

Group I: Arm III (olaparib, capivasertib) Experimental Treatment 3 Interventions

INTERMITTENT AZD5363 DOSING: Patients receive olaparib PO BID on days 1-28 (on days 5-28 of course 1 and alone on days -3 to -1 of week -1) and capivasertib PO BID for 4 days on and 3 days off (alone on days 1-4 of week 1).

Group II: Arm II (olaparib, vistusertib) Experimental Treatment 3 Interventions

INTERMITTENT AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 3-28 on course 1 and alone on days -5 to -3 of week -1) and vistusertib 4 PO BID for 2 days on and 5 days off (alone on days 1-2 of week 1).

Group III: Arm I (olaparib, vistusertib) Experimental Treatment 4 Interventions

CONTINUOUS AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1).

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

In a study involving 44 women with platinum-refractory ovarian cancer or advanced endometrial carcinoma, the mTOR inhibitor temsirolimus was found to be well tolerated with mild toxicity, but it did not meet the predefined efficacy criteria for progression-free survival.

Despite the overall lack of efficacy, some patients experienced long-lasting disease stabilization, indicating that temsirolimus may still have potential benefits for a subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). Emons, G., Kurzeder, C., Schmalfeldt, B., et al.[2016]

In the phase III SOLO1 trial, maintenance treatment with olaparib significantly improved progression-free survival in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, with 260 patients receiving olaparib compared to 131 on placebo.

The most common adverse events associated with olaparib, such as anemia and nausea, occurred early (within 3 months) but were manageable, with only a small number of patients needing to discontinue treatment, indicating a predictable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Colombo, N., Moore, K., Scambia, G., et al.[2022]

Olaparib (OLA) monotherapy showed a similar overall objective response rate (ORR) compared to chemotherapy (CT) in patients with relapsed ovarian cancer, with ORR of 24.3% for OLA and 28.3% for CT, indicating comparable efficacy.

In patients with platinum-resistant ovarian cancer (PROC) who had received more than four prior lines of treatment, OLA demonstrated a higher ORR of 22.9% compared to 0% for CT, suggesting that OLA may be more effective in heavily pretreated cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. Vanderstichele, A., Loverix, L., Busschaert, P., et al.[2022]

In a study of 65 patients with advanced serous ovarian cancer in mainland China, olaparib showed a median progression-free survival (PFS) of 4.2 months, with better outcomes for patients with BRCA mutations (5.3 months) compared to those with wild-type BRCA (3.1 months).

Patients receiving olaparib as maintenance therapy had significantly longer PFS (between 9.0 and 10.0 months) compared to those on active therapy (3.1 to 3.0 months), and the treatment was generally well-tolerated, with 87% of patients experiencing low-grade adverse events like fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world clinical outcomes of olaparib therapy in Chinese patients with advanced serous ovarian cancer treated in Macau. Cao, Y., Chen, H., Huang, Y., et al.[2021]

Maintenance treatment with olaparib significantly improves progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer, reducing the risk of disease progression or death by up to 80% compared to placebo, based on data from the SOLO1 trial involving various patient subgroups.

The benefits of olaparib are consistent across different baseline factors, including surgery type, chemotherapy response, and BRCA mutation status, indicating its broad efficacy as a treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial. DiSilvestro, P., Colombo, N., Scambia, G., et al.[2021]

Olaparib is an effective oral treatment for advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations, working by blocking DNA repair mechanisms in tumor cells, leading to selective cell death.

In clinical trials, olaparib significantly improved progression-free survival in patients with various types of ovarian cancer, and it is generally well tolerated, with mild side effects like nausea and fatigue being the most common.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of BRCA-mutated advanced ovarian cancer. Munroe, M., Kolesar, J.[2019]

Citations

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

Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer. [2021]

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

A randomized phase II trial of everolimus and letrozole or hormonal therapy in women with advanced, persistent or recurrent endometrial carcinoma: A GOG Foundation study. [2022]

4. England pubmed.ncbi.nlm.nih.gov

The rationale for mTOR inhibition in epithelial ovarian cancer. [2021]

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

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). [2016]

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

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. [2022]

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

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. [2022]

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

Real-world clinical outcomes of olaparib therapy in Chinese patients with advanced serous ovarian cancer treated in Macau. [2021]

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

Efficacy of Maintenance Olaparib for Patients With Newly Diagnosed Advanced Ovarian Cancer With a BRCA Mutation: Subgroup Analysis Findings From the SOLO1 Trial. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of BRCA-mutated advanced ovarian cancer. [2019]

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

Dual mTORC1/2 inhibition in a preclinical xenograft tumor model of endometrial cancer. [2021]