Sapanisertib + Serabelisib + Paclitaxel for Endometrial Cancer

Recruiting at 9 trial locations

Overseen By Medical Monitor

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Faeth Therapeutics

Must be taking: Platinum chemotherapy, Checkpoint inhibitors

Must not be taking: Strong CYP3A4 inhibitors, PPIs

Disqualifiers: CNS metastases, Active malignancy, Cardiovascular impairment, 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: Unknown

Duration: Up to 2 years

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 2, multicenter, open-label, single-arm study to evaluate the efficacy and safety of sapanisertib and serabelisib (PIKTOR) with paclitaxel in participants with advanced or recurrent endometrial cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong CYP3A4 inhibitors or inducers, and strong CYP1A2 inhibitors or inducers, at least 7 days before starting the study. You also cannot take PPIs or certain antacids during the study.

What data supports the effectiveness of the drug combination Sapanisertib, Serabelisib, and Paclitaxel for endometrial cancer?

A study showed that Sapanisertib, when combined with Paclitaxel, was investigated for treating advanced endometrial cancer, suggesting potential benefits. Additionally, PI3K inhibitors like Serabelisib have been explored as treatment options for advanced endometrial cancer, indicating possible effectiveness. ^{1 2 3 4 5}

Is the combination of Sapanisertib, Serabelisib, and Paclitaxel safe for humans?

The combination of Sapanisertib, Serabelisib, and Paclitaxel has been studied for safety in patients with advanced solid tumors. In one study, common side effects included anemia (low red blood cell count), neutropenia (low white blood cell count), and thrombocytopenia (low platelet count), but the treatment was generally considered to have a manageable safety profile. ^{4 6 7 8 9}

What makes the drug combination of Sapanisertib, Serabelisib, and Paclitaxel unique for endometrial cancer?

This drug combination is unique because it targets specific pathways involved in cancer growth: Sapanisertib inhibits mTORC1/2, and Serabelisib inhibits PI3K, both of which are important for cancer cell survival, while Paclitaxel is a chemotherapy drug that disrupts cell division. This combination aims to enhance the effectiveness of treatment by attacking the cancer cells from multiple angles. ^{3 4 10 11 12}

Eligibility Criteria

This trial is for women with advanced or recurrent endometrial cancer that can't be treated with surgery or radiation. They must have had 1-3 prior treatments, a specific gene alteration, and be in good physical condition. Participants need at least one measurable tumor and agree to use contraception if not postmenopausal or surgically sterile.

Inclusion Criteria

My cancer's gene alteration status for the PI3K/AKT/mTOR pathway is known.

I am fully active or can carry out light work.

I have at least one tumor that can be measured.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sapanisertib and serabelisib (PIKTOR) orally and paclitaxel intravenously

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Sapanisertib
• Serabelisib

Trial Overview The study tests the combination of two drugs, Sapanisertib and Serabelisib (PIKTOR), with Paclitaxel on patients with endometrial cancer. It's an open-label Phase 2 trial where all participants receive the same treatment to assess its effectiveness and safety.

Participant Groups

Group I: sapanisertib and serabelisib (PIKTOR) with paclitaxel Experimental Treatment 3 Interventions

Subjects will receive doses of sapanisertib and serabelisib (PIKTOR) administered orally and paclitaxel administered intravenously.

Who Is Running the Clinical Trial?

Faeth Therapeutics

Lead Sponsor

Trials

4

Recruited

170+

GOG Foundation

Collaborator

Trials

48

Recruited

18,500+

Findings from Research

In a Phase II study involving 67 patients with advanced or recurrent endometrial carcinoma, the PI3K inhibitor pilaralisib showed a low objective response rate of only 6.0%, indicating minimal antitumor activity.

Pilaralisib was generally well-tolerated, with the most common treatment-related side effects being rash (40.3%), diarrhea (37.3%), and fatigue (28.4%), suggesting a favorable safety profile despite limited efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Matulonis, U., Vergote, I., Backes, F., et al.[2022]

In a phase 3 trial involving 827 patients with advanced endometrial cancer, the combination of lenvatinib and pembrolizumab (LEN+PEMBRO) showed significant improvements in efficacy compared to the treatment of physician's choice (TPC), indicating it is a promising treatment option.

Health-related quality of life (HRQoL) assessments revealed that while LEN+PEMBRO had advantages in certain symptoms like dyspnoea and body image, TPC was favored for pain and appetite loss, suggesting that LEN+PEMBRO offers a favorable overall benefit/risk profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician's Choice. Lorusso, D., Colombo, N., Herraez, AC., et al.[2023]

In a study of 63 patients with advanced or recurrent endometrial cancers, the combination of carboplatin and paclitaxel showed high response rates, with 78% in advanced nonpapillary serous cancers and 60% in advanced papillary serous cancers.

The treatment demonstrated manageable toxicity, primarily hematologic, and resulted in significant survival outcomes, including a median failure-free survival of 23 months for advanced nonpapillary serous cancers and a 62% overall survival rate at 3 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. Hoskins, PJ., Swenerton, KD., Pike, JA., et al.[2022]

In a phase 2 study involving 241 patients with advanced endometrial cancer, the combination of sapanisertib and paclitaxel showed a median progression-free survival (PFS) of 5.6 months compared to 3.7 months for paclitaxel alone, although the primary endpoint was not statistically significant (p = 0.139).

The combination treatment resulted in a higher rate of grade ≥ 3 treatment-emergent adverse events (89.5% for paclitaxel+sapanisertib vs. 54.0% for paclitaxel alone), indicating increased toxicity, but it was still considered manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer. Han, SN., Oza, A., Colombo, N., et al.[2023]

In a study of 48 patients with high-risk stage III and IV endometrial cancer, the combination of paclitaxel and carboplatin (TC) after complete tumor resection resulted in a 3-year overall survival rate of 56% and a median overall survival of 47 months.

The treatment was well tolerated, with 90% of patients completing all planned cycles, and a median time to disease progression of 13 months, indicating that TC is an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study. Sovak, MA., Hensley, ML., Dupont, J., et al.[2015]

The combination of sapanisertib, a mTORC1/2 inhibitor, with carboplatin and paclitaxel showed a manageable safety profile in patients with tumors that have mTOR pathway alterations, with no unexpected toxicities reported.

Among 17 evaluable patients, there were signs of preliminary antitumor activity, with 2 achieving partial responses and a median progression-free survival of 3.84 months, indicating potential efficacy in advanced malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies. Alhalabi, O., Groisberg, R., Zinner, R., et al.[2023]

In a phase I study involving 61 patients with advanced solid tumors, the investigational drug sapanisertib (TAK-228) was found to be well tolerated, with maximum tolerated doses established for different administration schedules, and no significant differences in adverse events across treatment regimens.

TAK-228 demonstrated antitumor activity, particularly when combined with paclitaxel, showing objective response rates of 18% for the combination therapy and 12% for the daily administration, indicating its potential effectiveness in treating certain malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): tolerability and food effects of a milled formulation in patients with advanced solid tumours. Moore, KN., Bauer, TM., Falchook, GS., et al.[2022]

Sapanisertib, an oral mTORC1/mTORC2 inhibitor, showed a manageable safety profile in a Phase 1 study involving 31 patients with advanced solid tumors, with maximum tolerated doses identified for different dosing schedules.

Preliminary results indicated antitumor activity, with one complete response and nine partial responses observed, particularly in patients with renal cell carcinoma and endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. Voss, MH., Gordon, MS., Mita, M., et al.[2022]

The combination of sapanisertib, serabelisib, and paclitaxel was found to be safe and well tolerated in a Phase I trial involving 19 patients with advanced solid tumors, with manageable adverse effects such as decreased white blood cells and anemia.

Preliminary efficacy results were promising, showing an overall response rate of 47% and a clinical benefit rate of 73%, particularly in patients with specific genetic abnormalities, indicating potential effectiveness in a challenging treatment population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors. Starks, DC., Rojas-Espaillat, L., Meissner, T., et al.[2022]

In a study of 30 patients with advanced or recurrent endometrial cancer, paclitaxel demonstrated a response rate of 35.7%, with 14.3% achieving complete responses and 21.4% showing partial responses.

While paclitaxel was effective, it also caused significant side effects, including severe leukopenia in 18 patients and gastrointestinal toxicity in 5, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Ball, HG., Blessing, JA., Lentz, SS., et al.[2015]

In a phase II study involving 53 patients with persistent or recurrent carcinosarcoma of the uterus, paclitaxel demonstrated moderate clinical activity, with an overall response rate of 18.2%, including both complete and partial responses.

The most common side effect observed was neutropenia, indicating that while paclitaxel can be effective, it also carries risks that need to be monitored during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel in the treatment of carcinosarcoma of the uterus: a gynecologic oncology group study. Curtin, JP., Blessing, JA., Soper, JT., et al.[2022]

The combination of paclitaxel and carboplatin showed a promising response rate in patients with high-risk endometrial cancer, achieving complete responses in 45.5% and partial responses in 27.3% of the 11 evaluable patients.

However, the treatment was associated with significant toxicity, with 49.2% of patients experiencing severe leukopenia and 90.5% experiencing severe neutropenia, indicating the need for supportive care in a substantial number of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Evaluation of paclitaxel and carboplatin in patients with endometrial cancer]. Nakamura, T., Onishi, Y., Yamamoto, F., et al.[2015]

References

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

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Health-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician's Choice. [2023]

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

Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. [2022]

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

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer. [2023]

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

Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study. [2015]

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

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies. [2023]

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

Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): tolerability and food effects of a milled formulation in patients with advanced solid tumours. [2022]

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

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. [2022]

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

Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors. [2022]

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

A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. [2015]

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

Paclitaxel in the treatment of carcinosarcoma of the uterus: a gynecologic oncology group study. [2022]

12. Japan pubmed.ncbi.nlm.nih.gov

[Evaluation of paclitaxel and carboplatin in patients with endometrial cancer]. [2015]