Gemcitabine +/− MK-1775 for Ovarian Cancer

Not currently recruiting at 18 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 drugs

Disqualifiers: Gemcitabine, Brain metastases, HIV, 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

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

Compensation: Varies

Number of Visits: 7

Duration: Up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for ovarian, primary peritoneal, or fallopian tube cancer that has recurred after treatment. Researchers aim to determine if adding MK-1775 (also known as Adavosertib, a drug that blocks a protein aiding cancer cell repair) to the chemotherapy drug gemcitabine is more effective than gemcitabine alone. This combination could potentially halt cancer cell growth. Individuals diagnosed with these cancer types, which did not respond to previous platinum-based treatments, might be suitable candidates. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that the combination of gemcitabine hydrochloride and the WEE1 inhibitor MK-1775, also known as adavosertib, has been well-tolerated in past studies. For instance, administering adavosertib at a dose of 200 mg daily did not result in any unexpected side effects. Patients did not encounter any new safety issues.

In another study, using gemcitabine with adavosertib in patients with ovarian cancer proved generally safe for most participants. This indicates that combining these drugs does not introduce significant new risks beyond those already known for each drug individually.

While these findings are encouraging, they originate from studies at different stages. These studies help assess whether the treatment is safe enough for broader use. It is also crucial to remember that individual reactions may vary, so close monitoring remains essential during trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of gemcitabine hydrochloride with the WEE1 inhibitor, MK-1775, for ovarian cancer treatment. Most current treatments, like platinum-based chemotherapy, target rapidly dividing cancer cells indiscriminately. However, MK-1775 works differently by specifically inhibiting the WEE1 protein, which plays a role in cell cycle regulation, potentially leading to enhanced cancer cell death when combined with gemcitabine. This targeted approach might improve treatment effectiveness and reduce harm to healthy cells, making it a promising option for patients with ovarian cancer.

What evidence suggests that gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 might be an effective treatment for recurrent ovarian cancer?

Studies have shown that adding the drug MK-1775 (also called adavosertib) to gemcitabine can benefit patients with certain types of ovarian cancer. In this trial, one group of participants will receive the combination of MK-1775 and gemcitabine. Research indicates that this combination allows patients to live longer without their cancer worsening. Specifically, one study found that patients receiving both treatments had an average of 4.6 months before cancer progression. Additionally, 63.8% of patients experienced disease control, meaning their cancer did not worsen. This suggests that using MK-1775 with gemcitabine might be more effective than using gemcitabine alone, which is being studied in another group of this trial, in slowing cancer growth. ^{1 2 5 6 7}

Who Is on the Research Team?

Amit Oza, MD

Principal Investigator

University Health Network-Princess Margaret Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 (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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10792546/

Gemcitabine plus adavosertib for platinum-resistant/refractory ... In conclusion, our results show significantly prolonged progression-free survival and overall survival with the addition of adavosertib to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10345044/

A Phase Ib Study Assessing the Safety, Tolerability, and ... An overall DCR of 63.8% was observed across all cohorts, which included patients who had been previously treated for ovarian cancer (including ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02101775?term=AREA%5BInterventionSearch%5D(%22Gemcitabine%22)&rank=5

Gemcitabine Hydrochloride With or Without WEE1 Inhibitor ... This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride ...

4. ascopost.com ascopost.com/issues/july-25-2021/addition-of-adavosertib-to-gemcitabine-improves-outcomes-in-high-grade-serous-ovarian-cancer/

Addition of Adavosertib to Gemcitabine Improves ... At the time of final analysis (March 2019), median progression-free survival was 4.6 months (95% confidence interval [CI] = 3.6–6.4 months) in ...

5. onclive.com onclive.com/view/persistent-development-of-wee1-pathway-inhibitors-begins-to-pay-off

Persistent Development of WEE1 Pathway Inhibitors ... The addition of adavosertib led to an increase in diarrhea (75% vs 37%), vomiting (63% vs 27%), and anemia (53% vs 32%), respectively, compared ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2468294224000212

Safety, tolerability, pharmacokinetics, and antitumor activity ... Adavosertib 200 mg once daily was well tolerated, with no new safety concerns. •. Adavosertib monotherapy had limited antitumor activity in this patient ...

7. cancertreatmentreviews.com cancertreatmentreviews.com/article/S0305-7372(23)00022-1/pdf

A systematic review The results showed an 32% ORR, 5.5 months mPFS (95%CI 3.9–7.2) and median OS of 19.2 months (95%CI 12.4–19.2) which are somewhat longer than the.