Drug Combinations for Endometrial Cancer

Not currently recruiting at 861 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A4 inducers

Disqualifiers: HIV, Hepatitis B/C, Stroke, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effects of different drug combinations for treating endometrial cancer that has returned or does not respond to usual treatments. The medications aim to slow or stop tumor growth and prevent the cancer from spreading. People with endometrial cancer who have tried other treatments without success might be suitable candidates. Participants will receive either one drug or a combination, such as olaparib (Lynparza), cediranib, durvalumab (Imfinzi), and capivasertib (Truqap), to determine which is most effective. Those with clear cell histology are not eligible. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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

The trial requires a washout period (time without taking certain medications) for strong and moderate CYP3A inhibitors before starting the study treatments. If you are taking these types of medications, you will need to stop them 2 weeks before the trial for strong inhibitors and at least 1 week for moderate inhibitors. Other medications may also need to be reviewed by the trial team.

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

Research shows that the treatments in this trial have different safety levels based on past studies. Here's a simple breakdown for each treatment:

1. **Cediranib**: Studies indicate that cediranib is generally safe, and most people handle it well. Some patients needed to change their dose due to side effects, but studies involving stomach cancer and soft tissue sarcoma found no new safety issues.

2. **Cediranib and Durvalumab**: Research on these combined treatments suggests they are manageable, but there is a higher chance of severe side effects when used together. Some patients might experience more serious reactions.

3. **Olaparib and Durvalumab**: Patients generally handled this combination well, although it didn't always meet goals for slowing cancer growth. It is safe, but its effectiveness can vary.

4. **Olaparib**: Olaparib alone has been consistently safe, though some patients had significant side effects. More severe side effects were reported in some cases.

5. **Cediranib and Olaparib**: This combination is considered safe without unexpected harmful effects, but its effectiveness can depend on the type of cancer.

6. **Olaparib and Capivasertib**: Trials show no serious side effects with this pair, making it a promising option. It seems to be well-tolerated in patients with endometrial and other cancers.

Overall, these treatments are generally well-tolerated, but side effects can vary. Some combinations might lead to more severe reactions than others. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for endometrial cancer because they offer novel mechanisms of action compared to standard therapies like surgery, radiation, and hormonal treatments. Capivasertib targets the AKT pathway, involved in cancer cell growth, while Cediranib Maleate inhibits VEGF receptors, which may reduce tumor blood supply. Olaparib is a PARP inhibitor, disrupting cancer cell DNA repair, and Durvalumab is an immune checkpoint inhibitor enhancing immune response against cancer cells. These diverse approaches provide hope for more effective and personalized treatment options for patients with endometrial cancer.

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

Research has shown that cediranib maleate, one of the treatments in this trial, may help treat endometrial cancer that has returned or is unresponsive to other treatments. In studies, 12.5% of patients experienced tumor shrinkage, and 29% did not see their cancer worsen for six months. In this trial, some participants will receive cediranib maleate alone, while others will receive it combined with durvalumab. When combined with durvalumab, patients experienced a longer period without cancer growth—5.3 months compared to 1.9 months with just one drug.

Another group in this trial will receive olaparib alone, which has shown effectiveness in other types of cancer for about 4.8 months. Combining olaparib with durvalumab, as tested in this trial, has shown improved results. Additionally, using olaparib with capivasertib, another combination under study, demonstrated lasting benefits without serious side effects in endometrial cancer. Overall, these treatments may help stop tumor growth by blocking important enzymes and boosting the immune system. ^{1 2 4 6 7}

Who Is on the Research Team?

Helen J Mackay

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for women with certain types of recurrent or refractory endometrial cancer. Participants must have adequate organ function, controlled blood pressure, and no severe allergies to the drugs being tested. They should not be pregnant, must agree to use contraception, and cannot have had certain prior treatments or serious health conditions like bowel obstruction or heart issues.

Inclusion Criteria

Your white blood cell count is higher than 1.5 x 10^9/L within the last 28 days.

I have had Bevacizumab or one immune-checkpoint therapy, but not durvalumab, before joining this trial.

My thyroid function is normal, with no symptoms of issues.

Exclusion Criteria

I have not been in trials for specific cancer drugs before, except for bevacizumab or single-agent immune therapy.

You have had certain types of cancer within the last 5 years, ongoing severe side effects from previous cancer treatments, or a history of serious allergic reactions to specific medications.

I haven't had cancer treatment or been in a trial in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive various combinations of olaparib, cediranib, durvalumab, and capivasertib in 28-day cycles

Up to 5 years

Monthly visits for treatment cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, then every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Capivasertib
• Cediranib Maleate
• Durvalumab
• Olaparib

Trial Overview The study tests combinations of olaparib with durvalumab, cediranib with durvalumab, olaparib with capivasertib, and cediranib alone in patients whose endometrial cancer has returned or resisted treatment. These drugs aim to block tumor growth by targeting enzymes needed for cell growth or interfering with tumor cells' ability to spread.

How Is the Trial Designed?

Group I: Arm VII (cediranib maleate_reference group 2) Experimental Treatment 7 Interventions

Patients in reference group 1 receive cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

Group II: Arm VI (cediranib maleate, durvalumab) Experimental Treatment 8 Interventions

Patients receive cediranib maleate PO QD on days 1-5 each week and durvalumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

Group III: Arm V (olaparib, durvalumab) Experimental Treatment 8 Interventions

Patients receive olaparib PO BID on days 1-28 and durvalumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

Group IV: Arm IV (olaparib, capivasertib) Experimental Treatment 8 Interventions

Patients receive olaparib PO BID on days 1-28 and capivasertib PO BID on days 1-4 each week. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

Group V: Arm III (cediranib maleate, olaparib) Experimental Treatment 8 Interventions

Patients receive olaparib PO BID and cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

Group VI: Arm II (olaparib) Experimental Treatment 7 Interventions

Patients receive olaparib PO BID. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

Group VII: Arm I (cediranib maleate_reference group 1) Experimental Treatment 7 Interventions

Patients in reference group 1 receive cediranib maleate PO QD. Cycles repeat every 28 days in the absence of disease progression or unaccepted toxicity. Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy, CT, Echo or MUGA on study.

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

Approved in United States as Truqap for:

• Hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations

Approved in European Union as Truqap for:

• Locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations

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

In a phase II study involving 46 patients with advanced endometrial cancer, the combination of pembrolizumab with carboplatin and paclitaxel resulted in a high objective response rate (ORR) of 74.4%, significantly exceeding the historical control rate of 50%.

The treatment was generally well-tolerated, with common mild side effects like anemia and fatigue, while immune profiling indicated that responders had enriched CD8+ and CD4+ T cell populations, suggesting a potential mechanism of action related to immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. Barber, EL., Chen, S., Pineda, MJ., et al.[2023]

The combination of lenvatinib and pembrolizumab is effective for treating advanced endometrial carcinoma, particularly in patients who have not responded to prior therapies, with manageable safety profiles similar to each drug used alone.

Common adverse reactions include hypothyroidism (51% incidence), fatigue, hypertension, and nausea, which typically occur within the first 10 weeks of treatment and can be effectively managed with dose adjustments and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. Makker, V., Taylor, MH., Oaknin, A., et al.[2022]

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[2021]

Endometrial cancer has a better prognosis when detected early, but for recurrent or metastatic cases, the median survival is only about 12 months, highlighting the need for effective treatment options.

Recent trials show that combining doxorubicin, cisplatin, and paclitaxel significantly improves response rates and overall survival compared to the standard doxorubicin plus cisplatin regimen, suggesting a more effective approach for treating advanced endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in endometrial cancer. Obel, JC., Friberg, G., Fleming, GF.[2007]

A 50-year-old woman with stage IVB poorly differentiated endometrial cancer experienced a significant clinical complete response after receiving the PARP inhibitor Olaparib, following the identification of a BRIP1 mutation.

This case represents the first documented instance of a pathologic complete response in high-grade endometrioid endometrial cancer treated with a PARP inhibitor, highlighting the potential for targeted therapies in cases with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Pathologic Response to PARP Inhibitor Olaparib in a Patient with Stage IVB Recurrent Endometrioid Endometrial Adenocarcinoma. Senguttuvan, RN., Wei, C., Raoof, M., et al.[2023]

For patients with advanced or recurrent endometrial cancer, the combination of doxorubicin and cisplatin is the standard chemotherapy, achieving a response rate of 47-60%.

A new trial combining doxorubicin, cisplatin, and paclitaxel shows promise with a response rate of 73%, although its impact on survival has yet to be determined.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy of endometrial cancer revisited]. Fehr, MK., Wight, E., Haller, U.[2017]

The combination of pembrolizumab and lenvatinib has shown improved overall response rates (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced and recurrent endometrial cancer, particularly those who are microsatellite stable (MSS) or mismatch repair proficient (pMMR) after failing platinum-based chemotherapy.

This treatment regimen is considered safe and effective, but clinicians must monitor patients for potential toxicities and be prepared to adjust dosages as necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib combination therapy for advanced endometrial carcinoma. Walker, CA., Spirtos, AN., Miller, DS.[2023]

A phase II study of the PARP inhibitor olaparib confirmed its clinical benefits for cancer patients with inherited BRCA1 and BRCA2 mutations, particularly in advanced breast and ovarian cancers.

The study also provided evidence that olaparib is effective against pancreatic and prostate cancers, expanding its potential use in treating various cancer types associated with these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib shows promise in multiple tumor types. [2014]

A survey of oncologists in Italy revealed that while there is a good understanding of new treatments for endometrial cancer (EC), such as dostarlimab for MSI high patients, these innovations are not fully integrated into clinical practice, with only 13.3% performing all necessary molecular tests.

After the approval of dostarlimab, 75.6% of clinicians preferred it for second-line treatment in MSI high advanced EC patients, indicating a significant shift in treatment choice, while 77.8% plan to use lenvatinib plus pembrolizumab for MSS patients once approved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Metastatic Endometrial Cancer: Physicians' Choices Beyond the First Line. A MITO Survey. Giannone, G., Castaldo, D., Tuninetti, V., et al.[2022]

The standard first-line chemotherapy for metastatic or recurrent endometrial cancer, combining carboplatin and paclitaxel, shows objective response rates of 43-62% and median overall survival ranging from 13.2 to 37.0 months, indicating its effectiveness in this patient population.

Immune checkpoint inhibitors like pembrolizumab and dostarlimab have demonstrated promising results, achieving objective response rates of 27-47% in patients with microsatellite instability-high (MSI-H) endometrial cancer, highlighting a potential treatment avenue for highly pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue "Diagnosis and Management of Endometrial Cancer". Gadducci, A., Cosio, S.[2021]

In a phase II study involving 13 women with recurrent platinum-sensitive ovarian cancer, the combination of olaparib and cediranib showed greater biological activity than olaparib alone, indicated by significant decreases in IL-8 levels and increases in circulating endothelial cells (CEC).

Changes in CEC and IL-8 levels on treatment day 3 were associated with longer progression-free survival, suggesting these biomarkers could help predict patient response to the combination therapy, although further validation is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CECs and IL-8 Have Prognostic and Predictive Utility in Patients with Recurrent Platinum-Sensitive Ovarian Cancer: Biomarker Correlates from the Randomized Phase-2 Trial of Olaparib and Cediranib Compared with Olaparib in Recurrent Platinum-Sensitive Ovarian Cancer. Lee, JM., Trepel, JB., Choyke, P., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26186911/

A phase II evaluation of cediranib in the treatment of ... - PubMed Results: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01132820?cond=%22Cystadenocarcinoma%22&intr=%22Maleic%20acid%22&viewType=Table&rank=1

Cediranib Maleate in Treating Patients With Recurrent or ... This phase II trial studies the side effects and how well cediranib maleate works in treating patients with endometrial cancer that has failed to respond to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4642817/

A Phase II Evaluation of Cediranib in the Treatment ... A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall ...

4. mayo.edu mayo.edu/research/clinical-trials/cls-20442275

Clinical Trials Olaparib, cediranib maleate, and Wee1 inhibitor AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

5. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03660826/

Clinical Trial: NCT03660826 Olaparib, cediranib, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Durvalumab is a ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/20/13/3603/78400/Phase-II-Study-of-Cediranib-in-Patients-with

Phase II Study of Cediranib in Patients with Advanced ... Importantly, no new safety concerns were identified during this study. The majority of both GIST and STS patients required a cediranib dose reduction or pause ...

7. centerwatch.com centerwatch.com/clinical-trials/listings/NCT01132820/cediranib-maleate-in-treating-patients-with-recurrent-or-persistent-endometrial-cancer

Cediranib Maleate in Treating Patients With Recurrent or ... This phase II trial studies the side effects and how well cediranib maleate works in treating patients with endometrial cancer that has ...