Ipatasertib + Megestrol Acetate for Endometrial Cancer

Not currently recruiting at 168 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: AKT inhibitors, Strong CYP3A inhibitors

Disqualifiers: Diabetes, Hypercholesterolemia, Liver disease, others

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

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining ipatasertib and megestrol acetate is more effective than using megestrol acetate alone for treating endometrial cancer that has recurred or spread. Ipatasertib, a new potential drug, may inhibit tumor growth by blocking enzymes necessary for cell growth, while megestrol acetate reduces estrogen levels, which some tumors require for growth. The trial seeks participants with recurrent or metastatic endometrial cancer who have already undergone other treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new potential drug.

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

The trial does not specify if you need to stop taking your current medications, but you cannot have taken strong CYP3A inhibitors or inducers within 14 days before joining. It's best to discuss your current medications with the trial team to ensure there are no interactions.

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

Research has shown that megestrol acetate has been safely used to treat advanced breast and endometrial cancers. It is generally well-tolerated and has a strong safety record. Studies also indicate that ipatasertib can help fight tumors in endometrial cancer. However, since this trial is in its early stages, the main goal is to test the safety of using ipatasertib with megestrol acetate. Early trials like this are crucial for understanding possible side effects and determining the safest dose for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ipatasertib combined with megestrol acetate for endometrial cancer because it targets the cancer in a unique way. Most treatments for endometrial cancer, like progestins or chemotherapy, focus on hormone regulation or broadly attacking rapidly dividing cells. However, ipatasertib works differently by specifically inhibiting the Akt pathway, which is often overactive in cancers, potentially leading to more targeted destruction of cancer cells. This novel mechanism, when combined with the hormone therapy megestrol acetate, offers hope for improved effectiveness and precision in treating this cancer.

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

This trial will compare the effectiveness of ipatasertib combined with megestrol acetate versus megestrol acetate alone for treating endometrial cancer. Research has shown that the combination might be more effective than megestrol acetate alone. Megestrol acetate lowers estrogen levels, slowing the growth of cancer cells that require estrogen. Ipatasertib blocks enzymes necessary for tumor cell growth. Early findings suggest this combination might reduce cancer recurrence in some patients. These results offer promise for those facing recurring or spreading endometrial cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Michaela O. Grinsfelder

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for adults with grade 1 or 2 recurrent or metastatic endometrioid endometrial cancer. Participants can have had any number of prior treatments but must not have received hormonal therapy within the last 6 months. They should be able to take oral medication, have no severe liver disease, uncontrolled diabetes, significant heart issues, active infections requiring IV antibiotics, and agree to use contraception if they can bear children.

Inclusion Criteria

Participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 28 days following the last dose of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately

My heart function is classified as class 2B or better, despite my history of heart issues or treatments.

I have completed any hormonal cancer treatments at least 6 months ago.

Exclusion Criteria

I am not currently on IV antibiotics for an infection.

I have not been treated with AKT inhibitors before, but may have had PI3K or mTOR inhibitors.

I am not pregnant and not nursing, or I am willing to stop nursing.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase Ib Treatment

Patients receive megestrol acetate and ipatasertib orally once daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Regular visits for CT/MRI and blood sample collection

Phase II Treatment

Patients are randomized to receive either megestrol acetate alone or in combination with ipatasertib. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Regular visits for CT/MRI and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up occurs every 3 months for 2 years, then every 6 months for 3 years.

Up to 5 years

Follow-up visits every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipatasertib
• Megestrol Acetate

Trial Overview The trial is testing whether adding Ipatasertib to Megestrol Acetate improves treatment outcomes in patients with advanced endometrial cancer. Ipatasertib blocks enzymes that may help tumor cells grow while Megestrol Acetate lowers estrogen levels which some tumor cells need to grow. The study will determine the safety and optimal doses as well as compare effectiveness against using Megestrol alone.

How Is the Trial Designed?

Group I: Phase Ib (megestrol acetate, ipatasertib) Experimental Treatment 5 Interventions

Patients receive megestrol acetate PO QD on days 1-28 and ipatasertib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

Group II: Phase II (megestrol acetate, ipatasertib) Experimental Treatment 5 Interventions

Arm II: Patients receive megestrol acetate PO QD on days 1-28 and ipatasertib PO QD on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

Group III: Phase II (megestrol acetate) Active Control 4 Interventions

Arm I: Patients receive megestrol acetate PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI during screening, on study, and during follow-up. Patients also undergo collection of blood samples throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

A 71-year-old woman with recurrent, metastatic endometrial cancer experienced significant clinical stability and a good quality of life for approximately 57 months while treated with a combination of tamoxifen and megestrol acetate, highlighting the potential effectiveness of this endocrine therapy.

This case suggests that combination endocrine therapy can be a viable treatment option for patients with recurrent, ER/PR-positive endometrial cancer, offering substantial long-term benefits with minimal side effects, even after multiple prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma. Cheng, JM., Gaillard, S., Beavis, AL., et al.[2023]

Hormonal manipulation has been a long-standing treatment for advanced breast cancer, with various methods like surgical ablation and high doses of hormones showing significant tumor regression in sensitive patients.

Megace (megestrol acetate) is highlighted as a therapy option that aims to achieve effective responses while minimizing toxicity, reflecting the current trend in selecting treatments for advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Megestrol acetate in breast cancer--a panel discussion. McGuire, WL., Johnson, PA., Muss, HB., et al.[2019]

In a study of 26 young women with well-differentiated endometrioid carcinoma or atypical hyperplasia, 80.8% responded to treatment with megestrol acetate after hysteroscopic curettage, indicating its efficacy as a fertility-sparing option.

Despite the effectiveness, there was a notable recurrence rate of 23.1% after a median follow-up of 32 months, particularly among patients with infertility or PCOS, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective study of fertility-sparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young women. Shan, BE., Ren, YL., Sun, JM., et al.[2013]

In a study of 101 patients with advanced breast cancer, megestrol acetate showed a 26% improvement rate, indicating its potential efficacy as a treatment option.

The drug was well tolerated with no observed toxicity or endocrine effects, making it a favorable choice for initial hormonal therapy in postmenopausal patients with disseminated breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Further clinical studies with megestrol acetate in advanced breast cancer. Ansfield, FJ., Davis, HL., Ramirez, G., et al.[2019]

In a study of 28 patients with advanced or recurrent endometrial cancer, the combination of paclitaxel, carboplatin, and megestrol acetate resulted in a mean overall survival of 50.1 months and a mean progression-free interval of 40.2 months, indicating significant efficacy of this treatment regimen.

While myelosuppression was a common side effect, affecting 78% of patients with severe neutropenia, the toxicity was manageable, suggesting that the addition of hormonal therapy to chemotherapy may enhance survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with paclitaxel, carboplatin and megestrol acetate for the management of advanced stage or recurrent carcinoma of the endometrium: a phase II study. Bevis, KS., Kilgore, LC., Alvarez, RD., et al.[2015]

In a study of 66 patients with advanced endometrial cancer, the combination of megestrol and tamoxifen showed a similar response rate (19%) to megestrol alone (20%), indicating no significant clinical advantage of the combination therapy.

While megestrol alone had only mild to moderate side effects, the combination therapy resulted in more severe toxicities, including a life-threatening pulmonary embolism, suggesting that adding tamoxifen may increase risks without improving efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Pandya, KJ., Yeap, BY., Weiner, LM., et al.[2019]

In a study of 61 women with recurrent or advanced endometrial carcinoma, alternating treatment with megestrol acetate and tamoxifen resulted in a 27% overall response rate, with some patients experiencing responses lasting over 20 months.

The treatment was associated with manageable toxicity, including two cases of severe thromboembolic events, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Fiorica, JV., Brunetto, VL., Hanjani, P., et al.[2019]

Megestrol acetate is an effective hormonal therapy for advanced breast cancer, showing an overall response rate of 30%, comparable to tamoxifen, and has a strong safety profile.

It may be particularly beneficial for patients experiencing cancer cachexia due to its associated weight gain, and it could serve as a viable treatment option for those whose disease progresses during tamoxifen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of megestrol acetate for the treatment of advanced breast cancer. Sedlacek, SM.[2018]

Megestrol acetate has been shown to effectively inhibit the recurrence of endometrial hyperplasia and adenocarcinoma, which are conditions that can progress to invasive cancer if untreated.

In patients with inoperable endometrial adenocarcinoma, megestrol acetate not only treats the cancer but also increases survival rates in those with recurrent cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progestin therapy in lesions of the endometrium. Wentz, WB.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05538897

NCT05538897 | Testing the Addition of the AKT Inhibitor, ... The combination of ipatasertib and megestrol acetate may be more effective in treating endometrial cancer than megestrol acetate alone. Detailed Description.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10046539/

Do Not Forget about Hormonal Therapy for Recurrent ... The response rate on the megestrol plus tamoxifen arm with 42 eligible cases was found to be similar to single-agent progesterone at 19%, with a median survival ...

3. withpower.com withpower.com/trial/phase-2-carcinoma-endometrioid-2023-1b496

Ipatasertib + Megestrol Acetate for Endometrial Cancer Despite the effectiveness, there was a notable recurrence rate of 23.1% after a median follow-up of 32 months, particularly among patients with infertility or ...

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2024-0155.html

NRG-GY028: A phase IB and randomized Phase II trial of ... The combination of ipatasertib and megestrol acetate may be more effective in treating endometrial cancer than megestrol acetate alone. Resources and Links.

5. studyfinder.umn.edu studyfinder.umn.edu/studies/31981

nrg-gy028: a phase ib and randomized ... The combination of ipatasertib and megestrol acetate may be more effective in treating endometrial cancer than megestrol acetate alone. I'm interested.

6. nrgoncology.org nrgoncology.org/Clinical-Trials/Protocol/nrg-gy028?filter=nrg-gy028

NRG-GY028 Phase I: Determine the toxicity of ipatasertib in combination with megestrol acetate in women with metastatic grade 1-2 endometrioid endometrial cancer and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10552741/

Ipatasertib exhibits anti-tumorigenic effects and enhances ... Ipatasertib exhibits anti-tumorigenic effects and enhances sensitivity to paclitaxel in endometrial cancer in vitro and in vivo.