DT2216 + Paclitaxel for Ovarian Cancer

Recruiting at 1 trial location

Overseen By Elizabeth Stover, MD, PhD

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Elizabeth Stover, MD, PhD

Must not be taking: CYP3A4 inhibitors, CYP2C8 inducers

Disqualifiers: Active infections, CNS metastases, others

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

Compensation: Varies

Number of Visits: 2

Duration: Variable (up to 24 cycles)

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that participants stop taking any medications that are strong inhibitors or inducers of the enzymes CYP3A4 or CYP2C8 at least 2 weeks before starting the study. If you are taking such medications, you will need to discontinue them. It's important to discuss all your current medications with the study team to ensure there are no interactions.

What data supports the effectiveness of the drug combination DT2216 and Paclitaxel for ovarian cancer?

Paclitaxel is known to be effective in treating advanced ovarian cancer, especially in patients who do not respond to platinum-based treatments. It is often used in combination with other drugs to improve outcomes. ^{1 2 3 4 5}

What safety information is available for Paclitaxel in ovarian cancer treatment?

Paclitaxel, used in ovarian cancer treatment, can cause side effects like hypersensitivity (allergic reactions), leukopenia (low white blood cell count), neurotoxicity (nerve damage), and alopecia (hair loss). Premedication can reduce severe allergic reactions, and different infusion schedules can affect the severity of side effects like neutropenia (low levels of a type of white blood cell). ^{6 7 8 9 10}

How is the drug DT2216 + Paclitaxel unique for treating ovarian cancer?

The combination of DT2216 and Paclitaxel for ovarian cancer is unique because it aims to enhance the effectiveness of Paclitaxel, which less than 50% of ovarian cancers respond to, by potentially increasing the cancer cells' sensitivity to the drug. ^{1 3 9 11 12}

What is the purpose of this trial?

The purpose of this research study is determining the highest dose of the study drug DT2216 in combination with paclitaxel that can be safely and tolerably administered in recurrent ovarian cancer. The names of the study drugs involved in this study are: * DT2216 (a type of proteolysis-targeting chimera degrader of BCL-XL protein) * Paclitaxel (a type of antimicrotubule agent)

Research Team

Elizabeth Stover, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for individuals with recurrent ovarian cancer that has resisted platinum-based chemotherapy. Participants must have measurable disease and acceptable organ function. Specific details about inclusion or exclusion criteria are not provided, but typically these would cover health status, prior treatments, and other medical conditions.

Inclusion Criteria

Participants must meet specific laboratory criteria including absolute neutrophil count, platelets, total bilirubin, AST/ALT, aPTT, INR, serum albumin, and eGFR

Participants with known HIV infection should meet specific criteria

I can understand and am willing to sign the consent form.

Exclusion Criteria

Participants receiving any other investigational agents within a specified timeframe

Pregnant females are excluded from this study

I have previously received weekly paclitaxel for cancer recurrence.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive DT2216 and Paclitaxel in 28-day cycles with dose escalation and de-escalation

Variable (up to 24 cycles)

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

1 visit (in-person)

Long-term follow-up

Participants are assessed radiologically every 16 weeks after treatment

Variable

Treatment Details

Interventions

• DT2216
• Paclitaxel

Trial Overview The study is testing the highest dose of DT2216 that can be given safely with paclitaxel to patients with recurrent ovarian cancer. DT2216 targets a protein called BCL-XL to induce cancer cell death, while paclitaxel disrupts cell division.

Participant Groups

Group I: DT2216 + Paclitaxel Experimental Treatment 2 Interventions

Dose de-escalation and escalation for the DT2216 and Pacllitaxel combination will be guided using a Bayesian Optimal Interval (BOIN) design. Enrolled participants will complete: * Baseline visit * Imaging every 2 cycles * ECG Days 1, 8, and 15 of Cycle 1 and Day 1 of Cycle 2. * Research blood sample Days 1, 2, 4, 8, 15, 16, 18 and 22 of Cycle 1 and Day 1 of every cycle. * Cycle 1 (28 day cycles): * Days 1, 4, 8, 11, 15, 18, 22, and 25: Predetermined dose of DT2216 1x daily * Days 1, 8, 15: Predetermined dose of Paclitaxel 1x daily * Cycle 2 through end of treatment (28 day cycles): * Days 1, 4, 8, 11, 15, 18, 22, 25: Predetermined dose of DT2216 1x daily * Days 1, 8, 15: Predetermined dose of Paclitaxel 1x daily * End of treatment visit with imaging * 30 day follow up visit

Who Is Running the Clinical Trial?

Elizabeth Stover, MD, PhD

Lead Sponsor

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Dialectic Therapeutics, Inc

Industry Sponsor

Trials

1

Recruited

20+

American Society of Clinical Oncology

Collaborator

Trials

40

Recruited

148,000+

Findings from Research

Inhibiting Src family and Abl kinases using siRNAs or dasatinib significantly enhances the sensitivity of ovarian cancer cells to paclitaxel, as demonstrated in both cell cultures and HEY xenograft models.

The mechanism involves the induction of p27(Kip1), which promotes apoptosis by suppressing Bcl-2 and Cdk1 expression, leading to increased effectiveness of paclitaxel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Le, XF., Mao, W., He, G., et al.[2021]

Cytoreductive surgery followed by platinum-based chemotherapy, particularly with carboplatin, remains the standard treatment for advanced epithelial ovarian cancer, but most patients are not cured, highlighting the need for improved therapies.

Paclitaxel, a novel agent effective in platinum-resistant ovarian cancer, is being tested in combination with platinum compounds in clinical trials for previously untreated patients, aiming to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ovarian cancer: current status. Ozols, RF.[2015]

Paclitaxel and docetaxel, two taxanes used in treating ovarian cancer, have shown clinical activity, with response rates of 20-48% for paclitaxel and 33-35% for docetaxel in previously treated patients, indicating their efficacy even in platinum-resistant tumors.

Premedication with dexamethasone, diphenhydramine, and cimetidine can significantly reduce the risk of severe allergic reactions to taxanes to less than 3%, highlighting a safety measure for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Options for primary chemotherapy of epithelial ovarian cancer: taxanes. Trimble, EL., Arbuck, SG., McGuire, WP.[2018]

Paclitaxel has recently become a standard chemotherapy treatment for advanced ovarian cancer, especially when combined with platinum compounds, based on a large randomized trial by the Gynaecologic Oncology Group.

Ongoing clinical trials are investigating the optimal use of paclitaxel, including its dosage, administration schedule, and comparing the effectiveness and side effects of different platinum combinations (carboplatin vs. cisplatin).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

USA update on paclitaxel in ovarian cancer. Ozols, RF.[2019]

Docetaxel combined with carboplatin is a feasible and tolerable first-line treatment option for newly diagnosed epithelial ovarian cancer, showing no significant difference in progression-free or overall survival compared to the traditional paclitaxel and carboplatin combination in a study of 1,077 patients.

While docetaxel was associated with more myelosuppression, it resulted in fewer cases of neuropathy compared to paclitaxel, leading to better quality-of-life outcomes for patients receiving docetaxel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer. Vasey, PA.[2018]

Docetaxel shows comparable efficacy to paclitaxel in treating ovarian cancer, with a median progression-free survival of 16 months and a low neurotoxicity rate of 5%, significantly lower than the over 30% seen with paclitaxel.

In a large randomized trial involving 1077 patients, docetaxel combined with carboplatin demonstrated acceptable toxicity and treatment adherence, justifying further analysis of its safety and efficacy compared to the traditional paclitaxel-carboplatin regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The integration of docetaxel into first-line chemotherapy for ovarian cancer. Kaye, SB.[2019]

In a study comparing carboplatin combined with either paclitaxel or docetaxel in four ovarian carcinoma cell lines, both combinations showed a synergistic effect, enhancing the growth inhibitory impact on cancer cells.

The combination of carboplatin with paclitaxel produced a broader range of supra-additive effects across various concentrations compared to the carboplatin-docetaxel combination, suggesting that paclitaxel may be more effective in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin-paclitaxel- and carboplatin-docetaxel-induced cytotoxic effect in epithelial ovarian carcinoma in vitro. Engblom, P., Rantanen, V., Kulmala, J., et al.[2019]

The maximum tolerated dose (MTD) for the combination of intravenous docetaxel, intraperitoneal carboplatin, and intraperitoneal paclitaxel was established as docetaxel 75 mg/m², carboplatin AUC 6, and paclitaxel 60 mg/m², but this regimen was not feasible over four treatment cycles due to significant bone marrow toxicity.

Fifteen out of 40 evaluable patients experienced dose-limiting toxicities, including severe neutropenia and infections, indicating that while the treatment shows potential, adjustments such as reducing carboplatin to AUC 5 may be necessary for safer administration in women with advanced ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study with an expanded cohort to assess feasibility of intravenous docetaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with previously untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gould, N., Sill, MW., Mannel, RS., et al.[2021]

References

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

The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. [2021]

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

Treatment of ovarian cancer: current status. [2015]

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

Taxanes in ovarian cancer treatment. [2018]

4. France pubmed.ncbi.nlm.nih.gov

[Taxanes in the treatment of breast and ovarian cancers: current indications and results]. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

Activity of docetaxel in paclitaxel-resistant ovarian cancer cells. [2018]

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

Options for primary chemotherapy of epithelial ovarian cancer: taxanes. [2018]

7. England pubmed.ncbi.nlm.nih.gov

USA update on paclitaxel in ovarian cancer. [2019]

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

Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

The integration of docetaxel into first-line chemotherapy for ovarian cancer. [2019]

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

Carboplatin-paclitaxel- and carboplatin-docetaxel-induced cytotoxic effect in epithelial ovarian carcinoma in vitro. [2019]

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

A phase I study with an expanded cohort to assess feasibility of intravenous docetaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with previously untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Paclitaxel and docetaxel in breast and ovarian cancer. [2018]