Berzosertib + Carboplatin +/- Docetaxel for Prostate Cancer

Not currently recruiting at 25 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: LHRH agonists

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Brain metastases, Uncontrolled illness, 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: 21

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drugs to treat prostate cancer that continues to spread despite hormone therapy. It examines how well the drugs berzosertib (an experimental treatment) and carboplatin, with or without docetaxel, work together to stop cancer growth. The trial aims to determine if this combination is more effective than using carboplatin and docetaxel alone. Men with prostate cancer that has spread and who have tried at least two other treatments without success might be suitable for this study. 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 that you stop taking any oral anti-cancer medications at least 14 days before starting the study treatment. Additionally, you must discontinue any ototoxic or nephrotoxic medications at least 7 days before the first dose of carboplatin. If you are taking medications that strongly affect the enzyme CYP3A4, you will need to avoid them during the trial.

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

Research shows that patients generally tolerate the combination of berzosertib and carboplatin well. Previous studies found that berzosertib, when combined with other chemotherapy drugs like cisplatin or gemcitabine, was well-received by patients with advanced solid tumors. This indicates that using berzosertib with carboplatin might also be safe.

Carboplatin and docetaxel are common chemotherapy drugs, widely used to treat various types of cancer. Doctors are familiar with their side effects and know how to manage them.

Overall, while any treatment can have side effects, evidence suggests that these drug combinations are generally manageable and tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine berzosertib, a novel ATR kinase inhibitor, with traditional chemotherapy agents like carboplatin and docetaxel to potentially enhance effectiveness against prostate cancer. Unlike standard treatments that primarily focus on disrupting cancer cell division, berzosertib targets the ATR pathway, which is crucial for repairing DNA damage in cancer cells. This unique approach might make cancer cells more vulnerable to chemotherapy, improving outcomes. Additionally, patients who don't respond to initial treatment with docetaxel and carboplatin have the opportunity to switch to the experimental combination of berzosertib and carboplatin, offering a backup plan that could be more effective.

What evidence suggests that this trial's treatments could be effective for metastatic castration-resistant prostate cancer?

In this trial, participants will receive different treatment combinations to evaluate their effectiveness in treating advanced prostate cancer. Research has shown that berzosertib, when combined with carboplatin, might help treat advanced prostate cancer by inhibiting the enzymes necessary for cancer cell growth. In Arm B of this trial, participants will receive this combination. Studies suggest that adding another drug, docetaxel, could enhance this treatment's effectiveness. In Arm A, participants will receive either docetaxel with carboplatin or carboplatin alone. Although the combination of berzosertib and carboplatin has shown promise, it has resulted in fewer positive responses compared to other treatments. However, it remains a potential option for those whose cancer has worsened despite other treatments. Researchers continue to study this combination to assess its efficacy and safety. ^{1 2 6 7 8}

Who Is on the Research Team?

Atish D Choudhury

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for men with metastatic castration-resistant prostate cancer that has progressed despite previous treatments. Participants must have a low testosterone level, adequate organ function, and no severe side effects from past cancer therapies. They should not have brain metastases or active infections and must not be on certain drugs that could interact with the study medication.

Inclusion Criteria

My prostate cancer is confirmed and getting worse.

My cancer has spread, shown by scans, and I have low testosterone levels.

I have previously been treated with mTOR inhibitors, TKIs, or biologic therapies.

Exclusion Criteria

I have been treated with platinum-based drugs or ATR inhibitors for prostate cancer.

I am on medication that could harm my hearing or kidneys and cannot stop taking it.

I do not have any uncontrolled illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either docetaxel and carboplatin or carboplatin and berzosertib. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30-42 days

What Are the Treatments Tested in This Trial?

Interventions

• Berzosertib (M6620)
• Carboplatin
• Docetaxel

Trial Overview The trial is testing the effectiveness of berzosertib (M6620) combined with carboplatin, with or without docetaxel, in treating advanced prostate cancer. Berzosertib blocks enzymes needed for cell growth while carboplatin and docetaxel are chemotherapy drugs aiming to kill or stop the spread of tumor cells.

How Is the Trial Designed?

Group I: Arm B (carboplatin, berzosertib) Experimental Treatment 3 Interventions

Patients receive carboplatin IV over 30 minutes on day 1 and berzosertib IV over 60-90 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (docetaxel, carboplatin) Active Control 3 Interventions

Patients receive docetaxel IV over 60 minutes and carboplatin IV over 30 minutes, or carboplatin alone on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who have PSA progression or radiographic progression may crossover to Arm B.

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

In a study of 83 Chinese patients with metastatic hormone-refractory prostate cancer, docetaxel plus prednisone showed a higher efficacy compared to mitoxantrone plus prednisone, with 43.2% of patients achieving a complete or partial response versus 33.3% for mitoxantrone.

Docetaxel plus prednisone also provided better PSA control, with an average time to PSA progression of 37.8 weeks compared to 25.3 weeks for mitoxantrone, although it was associated with slightly higher toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel plus prednisone versus mitoxantrone plus prednisone for metastatic hormone-refractory prostate cancer in Chinese patients: experience of a single center. Zhang, HL., Ye, DW., Yao, XD., et al.[2018]

In a study of 310 patients with castration-resistant prostate cancer (CRPC), the combination of taxane-estramustine-carboplatin (TEC) chemotherapy resulted in a significant prostate-specific antigen (PSA) response rate of 69%.

The 12-month survival estimate for patients receiving TEC chemotherapy was 79%, which is notably higher than the median predicted survival of 59%, indicating that TEC may provide substantial clinical benefits in CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials. Regan, MM., O'Donnell, EK., Kelly, WK., et al.[2021]

Docetaxel is the first treatment to significantly improve survival rates in patients with hormone-refractory prostate cancer, and it is now being tested in earlier stages of the disease to prevent recurrence in high-risk patients.

Pilot studies indicate that using docetaxel as a neo-adjuvant treatment can be done safely without increasing surgical risks, and ongoing randomized trials will further assess its effectiveness when combined with hormonal therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-risk localized prostate cancer: integrating chemotherapy. Oh, WK.[2018]

Docetaxel has shown significant effectiveness as a single agent in treating hormone refractory prostate cancer, achieving a 42% prostate-specific antigen response rate in four phase-II studies.

Combining docetaxel with estramustine may enhance the response rate, but it also increases the risk of toxicity, and further evaluation in ongoing phase-III studies will clarify its overall role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Significance of docetaxel in the chemotherapy of hormone-refractory prostate cancer]. Wolff, JM.[2018]

Docetaxel-based treatments have shown effectiveness in managing advanced, androgen-independent prostate cancer, achieving significant palliative responses and reducing PSA levels by over 50% in patients.

Ongoing phase III trials are expected to provide crucial data on the impact of docetaxel on overall survival, while preliminary studies suggest that combining docetaxel with other novel agents is safe and may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel in the integrated management of prostate cancer. Current applications and future promise. Logothetis, CJ.[2018]

Docetaxel shows a 42% response rate in treating androgen-independent prostate cancer based on four Phase II studies, indicating its significant efficacy as a single-agent therapy.

Combining docetaxel with estramustine may enhance response rates but also increases toxicity, and ongoing Phase III studies are expected to clarify the best use of docetaxel in treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel (taxotere) in the treatment of prostate cancer. Beer, TM., El-Geneidi, M., Eilers, KM.[2018]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.5034

A phase 2 study of berzosertib (M6620) in combination with ... Carbo+berzo led to fewer overall responses and a higher rate of grade 3 or higher TrAEs compared to carbo+doce.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03517969?cond=berzosertib&viewType=Table&rank=10

Study Details | NCT03517969 | M6620 and Carboplatin ... Giving M6620, carboplatin and docetaxel may work better in treating patients with metastatic castration-resistant prostate cancer compared to carboplatin and ...

3. dana-farber.org dana-farber.org/clinical-trials/19-715

A Phase 2 Study of M6620 in Combination with ... This phase II trial studies how well berzosertib (M6620) and carboplatin with or without docetaxel works in treating patients with castration-resistant ...

4. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT03517969

M6620 and Carboplatin With or Without Docetaxel in ... Giving M6620, carboplatin and docetaxel may work better in treating patients with metastatic castration-resistant prostate cancer compared to carboplatin and ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8367944/

Phase 1 study of the ATR inhibitor berzosertib in combination ... Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in ...

6. nature.com nature.com/articles/s41416-021-01405-x

Phase 1 study of the ATR inhibitor berzosertib (formerly ... Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.6_suppl.TPS252

A phase II study of M6620 in combination with carboplatin ... This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC.

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03517969/

Clinical Trial: NCT03517969 This phase II trial studies how well berzosertib (M6620) and carboplatin with or without docetaxel works in treating patients with castration- ...