Gemcitabine +/− MK-1775 for Ovarian Cancer

Recruiting at 17 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: Up to 1 year

124 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of time. Gemcitabine hydrochloride may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA, molecules that contain instructions for the proper development and functioning of cells), which in turn stops the tumor from growing. The protein WEE1 may help to repair the damaged tumor cells, so the tumor continues to grow. WEE1 inhibitor MK-1775 may block the WEE1 protein activity and may increase the effectiveness of gemcitabine hydrochloride by preventing the WEE1 protein from repairing damaged tumor cells without causing harm to normal cells. It is not yet known whether gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 may be an effective treatment for recurrent ovarian, primary peritoneal, or fallopian tube cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that affect the CYP3A4 enzyme at least two weeks before starting the study and continue to avoid them during the trial and for two weeks after the last dose. If you are taking any of these medications, you should discuss with your doctor about safely discontinuing them.

What data supports the effectiveness of the drug Gemcitabine for ovarian cancer?

Gemcitabine has shown consistent activity as a single-agent in platinum-resistant ovarian cancer, with remission rates of nearly 20% and a favorable toxicity profile. It has also been combined with other drugs like carboplatin, showing potential activity in clinical trials. ^{1 2 3 4 5}

Is the combination of Gemcitabine and MK-1775 safe for treating ovarian cancer?

Gemcitabine, also known as Gemzar, has been used in treating various cancers, including ovarian cancer, and is generally well tolerated with manageable side effects like mild blood-related issues and nausea. It has been safely combined with other drugs, showing a favorable safety profile in different cancer treatments. ^{1 2 3 6 7}

What makes the drug Gemcitabine unique for treating ovarian cancer?

Gemcitabine is unique for treating ovarian cancer because it has a novel mechanism of action and shows promising activity in patients who are resistant to platinum-based treatments, with a favorable side-effect profile. It is often combined with other drugs like carboplatin to enhance its effectiveness, making it a valuable option for both treated and untreated ovarian cancer patients. ^{1 2 8 9 10}

Research Team

Amit Oza, MD

Principal Investigator

University Health Network-Princess Margaret Hospital

Eligibility Criteria

This trial is for patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer who are platinum-resistant or have platinum-refractory disease. They must have a life expectancy over 3 months, acceptable blood counts and organ function, and be able to tolerate oral medication without an active bowel obstruction. Women of childbearing potential must use contraception.

Inclusion Criteria

Your blood clotting tests should be within a certain range.

Your hemoglobin level is at least 90 grams per liter.

You are expected to live for more than 3 months.

Exclusion Criteria

You have had allergic reactions to drugs similar to AZD 1775 or gemcitabine.

You have brain metastases that are unstable and causing symptoms.

Pregnant and breastfeeding women are excluded from this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 in 28-day cycles

Up to 1 year

Visits on days 1, 8, and 15 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Every 6-8 weeks

Treatment Details

Interventions

• Adavosertib
• Gemcitabine Hydrochloride

Trial Overview The study compares the effectiveness of gemcitabine hydrochloride alone versus combined with WEE1 inhibitor MK-1775 in treating certain cancers that have returned after treatment. The aim is to see if blocking WEE1 protein activity with MK-1775 enhances the impact of gemcitabine by preventing tumor cell repair.

Participant Groups

Group I: Arm I (WEE1 inhibitor MK-1775, gemcitabine hydrochloride) Experimental Treatment 5 Interventions

Patients receive WEE1 inhibitor MK-1775 PO on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (placebo, gemcitabine hydrochloride) Active Control 5 Interventions

Patients receive placebo PO on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride as patients in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Gemcitabine Hydrochloride is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Gemzar for:

• Non-small cell lung cancer
• Pancreatic cancer
• Breast cancer
• Ovarian cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Non-small cell lung cancer
• Breast cancer
• Ovarian cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Non-small cell lung cancer
• Breast cancer
• Ovarian cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Non-small cell lung cancer
• Breast cancer
• Ovarian cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Gemcitabine has shown promising results as a single-agent treatment for platinum-resistant ovarian cancer, achieving remission rates of nearly 20% with a favorable safety profile.

Combining gemcitabine with carboplatin has been explored in phase I and II trials, showing potential for improved efficacy in treating ovarian cancer, and further combinations with other agents are being actively researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in ovarian cancer. Orlando, M., Mandachain, M.[2022]

Gemcitabine (GEMZAR) has shown to be an effective treatment for non-small-cell lung cancer (NSCLC) with a response rate of about 21% as a single agent, and it has a mild toxicity profile, making it suitable for combination therapies.

When combined with cisplatin, gemcitabine achieved higher response rates ranging from 38% to 54% and median survival times of 8.4 to 14.3 months, with manageable side effects, indicating its potential as a preferred treatment option in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination studies with gemcitabine in the treatment of non-small-cell lung cancer. Steward, WP.[2022]

Gemcitabine hydrochloride is an effective chemotherapy agent for advanced pancreatic cancer, demonstrating good tolerability and the ability to be administered safely on an outpatient basis.

The side effects associated with gemcitabine are manageable with proper monitoring and can be reversed through dose adjustments, highlighting the importance of oncology nurses in patient education and symptom management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New agents in gastrointestinal malignancies: Part 2: Gemcitabine in clinical practice. Stucky-Marshall, L.[2022]

The human ovarian carcinoma cell line AG6000 developed significant resistance to gemcitabine (dFdCyd), with the IC50 increasing from 0.6 nM in the sensitive A2780 line to 92 µM in AG6000, indicating a stable resistance phenotype primarily due to a deficiency in deoxycytidine kinase (dCK).

AG6000 not only showed resistance to gemcitabine but also to other drugs that require dCK for activation, such as 1-beta-D-arabinofuranosylcytosine and 5-aza-2'-deoxycytidine, suggesting a broader mechanism of resistance that does not involve P-glycoprotein induction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and molecular characterization of a 2',2'-difluorodeoxycytidine-resistant variant of the human ovarian carcinoma cell line A2780. Ruiz van Haperen, VW., Veerman, G., Eriksson, S., et al.[2022]

Gemcitabine is an effective treatment for various solid tumors, including non-small-cell lung cancer and pancreatic cancer, with promising results also seen in breast and bladder cancers, based on phase II studies.

The drug has a favorable side-effect profile and may enhance the effectiveness of other DNA-damaging agents, suggesting its potential for use in combination therapies and different treatment schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of gemcitabine in the treatment of other tumours. Carmichael, J.[2022]

References

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

Cross-resistance in the 2',2'-difluorodeoxycytidine (gemcitabine)-resistant human ovarian cancer cell line AG6000 to standard and investigational drugs. [2022]

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

Gemcitabine in ovarian cancer. [2022]

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

A phase II study of fixed dose rate gemcitabine in patients with relapsed müllerian tumors. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

A case of drug resistant clear cell ovarian cancer showing responsiveness to gemcitabine at first administration and at re-challenge. [2022]

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

Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Combination studies with gemcitabine in the treatment of non-small-cell lung cancer. [2022]

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

New agents in gastrointestinal malignancies: Part 2: Gemcitabine in clinical practice. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Role of gemcitabine in ovarian cancer treatment. [2022]

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

Development and molecular characterization of a 2',2'-difluorodeoxycytidine-resistant variant of the human ovarian carcinoma cell line A2780. [2022]

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

The role of gemcitabine in the treatment of other tumours. [2022]