Drug Combinations for Endometrial Cancer

Recruiting at 823 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

286 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination for endometrial cancer?

The combination of pembrolizumab and lenvatinib has shown effectiveness in treating advanced endometrial carcinoma, improving outcomes like overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared to other therapies. This suggests that combining different drugs can be beneficial in treating this type of cancer. ^{1 2 3 4 5}

Is the drug combination generally safe for humans?

Olaparib, a drug used in cancer treatment, has been studied in combination with other drugs like durvalumab and cediranib. These studies have shown that the combination can be effective, but they also highlight the importance of monitoring for side effects, as some patients have experienced severe reactions. ^{6 7 8 9 10}

How is the drug combination of Capivasertib, Cediranib Maleate, Durvalumab, and Olaparib unique for treating endometrial cancer?

This drug combination is unique because it combines multiple mechanisms of action, including targeting cancer cell growth pathways and enhancing the immune system's ability to fight cancer, which may offer a novel approach compared to traditional chemotherapy or single-agent therapies for endometrial cancer. ^{4 11 12 13 14}

What is the purpose of this trial?

This trial tests different drug combinations to treat endometrial cancer that has come back or doesn't respond to usual treatments. The drugs work by either blocking enzymes needed for cancer growth or helping the immune system attack the cancer. The goal is to find the most effective treatment combination.

Research Team

Helen J Mackay

Principal Investigator

NRG Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: 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 II: 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 III: 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 IV: Arm III (cediranib maleate, olaparib) Experimental Treatment 9 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 V: 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 VI: Arm I (cediranib maleate) Experimental Treatment 8 Interventions

Patients 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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2023]

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

An impressive response to pazopanib in a patient with metastatic endometrial carcinoma. [2021]

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

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. [2022]

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

Pembrolizumab plus lenvatinib combination therapy for advanced endometrial carcinoma. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Management of Metastatic Endometrial Cancer: Physicians' Choices Beyond the First Line. A MITO Survey. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Complete Pathologic Response to PARP Inhibitor Olaparib in a Patient with Stage IVB Recurrent Endometrioid Endometrial Adenocarcinoma. [2023]

7. Switzerland 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. [2020]

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

A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer. [2023]

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

Olaparib shows promise in multiple tumor types. [2014]

10. England 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. [2021]

11. Switzerland 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". [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

[Chemotherapy of endometrial cancer revisited]. [2017]

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

Chemotherapy in endometrial cancer. [2007]

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

The role of immunotherapy in advanced and recurrent MMR deficient and proficient endometrial carcinoma. [2023]