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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new combinations of medications for certain cancers, such as endometrial, ovarian, and triple-negative breast cancer, that have returned after treatment. The goal is to identify the safest and most effective doses of these drug combinations to halt cancer cell growth. Individuals diagnosed with one of these cancers, which has recurred despite previous treatments, might be suitable for this trial. The trial includes AZD2014 and AZD5363, which are mTOR/AKT inhibitors, and Olaparib (also known as Lynparza), a PARP inhibitor. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive these new drug combinations.

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

Researchers are investigating the optimal dose and side effects of combining olaparib with vistusertib. Some studies have shown that patients taking this combination experienced tumor shrinkage or halted cancer growth temporarily. However, like many treatments, side effects can occur, and researchers are closely monitoring them.

For those interested in the olaparib and capivasertib combination, early findings indicate it has undergone safety testing. Some patients responded well to this treatment in studies. Nonetheless, side effects are possible and remain a key focus of the research.

Both combinations are in early testing stages, with the primary goal of ensuring safety. While both have shown promise in shrinking tumors, safety and side effects are the main focus at this stage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they represent a novel approach to tackling endometrial and ovarian cancer. Unlike standard treatments that often focus on disrupting cell division or killing cancer cells directly, these investigational drugs target specific cellular pathways critical for cancer growth. Olaparib is a PARP inhibitor that interferes with cancer cells' ability to repair their DNA, making them more vulnerable to damage. Vistusertib and capivasertib focus on inhibiting the mTOR and AKT pathways, respectively, which are essential for cancer cell survival and proliferation. This multi-pronged attack on cancer cells through different mechanisms offers hope for more effective treatment options with potentially fewer side effects.

What evidence suggests that this trial's treatments could be effective for endometrial and ovarian cancer?

This trial will evaluate different combinations of treatments for endometrial and ovarian cancer. Research has shown that combining olaparib and vistusertib, which participants in Arms I and II of this trial may receive, may help treat certain cancers. In one study, 31% of patients with endometrial cancer and 8% of those with ovarian cancer responded to the treatment. Overall, 37% of the participants experienced some clinical benefit.

For the combination of olaparib and capivasertib, which participants in Arm III of this trial may receive, studies have found it effective in treating ovarian and endometrial cancers without causing serious side effects. In another study, 50% of endometrial cancer patients responded to this treatment. These treatments work by blocking enzymes that cancer cells need to grow, which is why researchers are testing their effectiveness. ^{2 4 5 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?

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

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8639651/

Phase 1b dose expansion and translational analyses ... Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS5629

A randomized phase II study comparing single-agent ... Results from the first set of arms established improved PFS for combination cediranib/olaparib over C alone, but did not meet its prespecified ...

3. onclive.com onclive.com/view/recent-developments-in-ovarian-and-endometrial-cancers-stir-excitement-among-clinicians

Recent Developments in Ovarian and Endometrial ... Treatment with the PARP inhibitor led to a significant improvement in investigator assessed median progression-free survival (PFS) compared with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7383016/

PARP Inhibitors in Endometrial Cancer: Current Status and ... Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(20)37810-8/pdf

Phase I expansion of olaparib (PARP inhibitor) and ... Seven had confirmed partial response including 1 ovarian, 4 endometrial and 2 triple negative breast cancer pts. RR among endometrial cancer pts was 50% (4/8).

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2014-01973

Olaparib and Vistusertib or Capivasertib in Treating ... Olaparib, vistusertib, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Eligibility Criteria ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02208375

NCT02208375 | mTORC1/2 Inhibitor AZD2014 or the Oral ... To determine the safety and observed toxicities of the combination of AZD2014 + olaparib and AZD5363 + olaparib in patients with recurrent endometrial, ...