Dasatinib + Temsirolimus + Cyclophosphamide for Cancer

Overseen By Wafik Zaky, MBBCH

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticoagulants, Anticonvulsants, ACE inhibitors, others

Disqualifiers: Cardiovascular disease, HIV, others

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

Compensation: Varies

Number of Visits: 3

Duration: 24 weeks

14 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of dasatinib and temsirolimus when given together with cyclophosphamide in treating patients with solid tumors that have spread to other places in the body, have come back, or have not respond to previous treatment. Dasatinib and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving dasatinib and temsirolimus together with cyclophosphamide may be a better treatment for advanced solid tumors.

Will I have to stop taking my current medications?

The trial requires you to stop certain medications before starting, such as liver enzyme-inducing anticonvulsants, anti-thrombotic or anti-platelet agents, and drugs that cause significant prolonged QT. You must also stop any CYP3A4 inhibitors or inducers at least 7 days before starting dasatinib.

What data supports the effectiveness of the drug combination Dasatinib, Temsirolimus, and Cyclophosphamide for cancer?

Research shows that Cyclophosphamide, when used in combination with other drugs like cisplatin, has been effective in treating advanced ovarian cancer, with a notable response rate and progression-free survival. Although this does not directly address the combination with Dasatinib and Temsirolimus, it suggests that Cyclophosphamide can be an effective component in cancer treatment regimens. ^{1 2 3 4 5}

Is the combination of Dasatinib, Temsirolimus, and Cyclophosphamide safe for humans?

Dasatinib (Sprycel) has been used to treat certain types of leukemia, but it can cause side effects like myelosuppression (reduced bone marrow activity) and pleural effusions (fluid around the lungs). Temsirolimus (Torisel) has been tested in patients with advanced cancer to determine safe dosage and side effects. While these drugs have been studied individually, specific safety data for their combined use with Cyclophosphamide is not provided in the available research. ^{6 7 8 9 10}

What makes the drug combination of Dasatinib, Temsirolimus, and Cyclophosphamide unique for cancer treatment?

This drug combination is unique because it combines Dasatinib, which targets specific proteins involved in cancer cell growth, with Temsirolimus, an mTOR inhibitor that blocks cancer cell division, and Cyclophosphamide, a chemotherapy drug that damages cancer cell DNA. This multi-targeted approach may offer a novel way to attack cancer cells from different angles, potentially improving treatment effectiveness. ^{11 12 13 14 15}

Research Team

Wafik T Zaky

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients under 21 with advanced solid tumors, including brain tumors, that have spread or not responded to treatment. They must have proper liver and kidney function, stable neurological status if they have brain tumors, and a life expectancy of at least 12 weeks. Patients should not be pregnant or breastfeeding, HIV positive, or have had certain recent health issues like heart disease.

Inclusion Criteria

My condition is stable, and my tumor can be measured or evaluated.

I am between 12 months and 21 years old.

I don't have trouble breathing at rest, can exercise, and my oxygen level is above 94%.

Exclusion Criteria

I have never been treated with dasatinib or temsirolimus.

I have had recent bleeding in a tumor, GI bleeding, heart disease, or am on blood thinners.

Pregnant or breast-feeding women will not be entered on this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dasatinib orally twice daily, cyclophosphamide orally once daily, and temsirolimus intravenously on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses.

24 weeks

3 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cyclophosphamide
• Dasatinib
• Temsirolimus

Trial Overview The trial tests the combination of dasatinib and temsirolimus with cyclophosphamide in patients with recurrent or resistant solid tumors. It aims to find the safest doses and observe how these drugs might stop tumor growth by inhibiting specific enzymes needed for cell division.

Participant Groups

Group I: Treatment (dasatinib, cyclophosphamide, temsirolimus) Experimental Treatment 4 Interventions

Patients receive dasatinib PO BID on days 1-21, cyclophosphamide PO QD on days 1-21, and temsirolimus IV over 30-60 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing stable disease or better may continue treatment with the approval of the Study Chair.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Dasatinib is an effective targeted therapy for chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia, showing strong hematologic, cytogenetic, and molecular responses in patients resistant or intolerant to imatinib.

Despite its efficacy, dasatinib can cause significant side effects like myelosuppression and pleural effusions, particularly in advanced-phase patients; however, recent dose optimization has reduced these adverse events without affecting the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Cony-Makhoul, P., Bergeron, A., Corm, S., et al.[2015]

In a study involving 63 patients with advanced cancer, temsirolimus was found to be generally well tolerated, with a maximum tolerated dose established at 15 mg/m²/day for heavily pretreated patients and 19 mg/m²/day for minimally pretreated patients.

The treatment showed promising preliminary antitumor activity, with one patient achieving a confirmed partial response lasting 12.7 months, and several others showing stable disease for over 24 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Hidalgo, M., Buckner, JC., Erlichman, C., et al.[2014]

Dasatinib, approved by the FDA for treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL), showed a major cytogenetic response rate of 45% in chronic phase CML and significant hematologic response rates in other phases of CML and Ph(+) ALL, indicating its efficacy in patients resistant to prior therapies.

The treatment was associated with common side effects such as myelosuppression, bleeding, and fluid retention, highlighting the importance of monitoring patient safety during dasatinib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Brave, M., Goodman, V., Kaminskas, E., et al.[2023]

Dasatinib, a multiple kinase inhibitor, is rapidly absorbed in the body after oral administration, with a peak concentration reached in about 30 minutes and a short elimination half-life of less than 4 hours, indicating efficient absorption and metabolism.

Most of dasatinib is eliminated through feces (85%), and while several metabolites are formed, they are not expected to significantly contribute to the drug's therapeutic effects, as the active metabolites do not show strong inhibitory activity against key kinases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and disposition of dasatinib after oral administration to humans. Christopher, LJ., Cui, D., Wu, C., et al.[2015]

A clinical study involving 56 volunteers demonstrated that the generic dasatinib tablet (YiNiShu®) is bioequivalent to the branded version (Sprycel®) under both fasting and fed conditions, indicating similar pharmacokinetic profiles.

Both dasatinib formulations showed a good safety profile, confirming that patients can expect comparable efficacy and safety when using either version of the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Wang, Y., Xue, J., Su, Z., et al.[2023]

A study involving 108 patients with refractory or relapsing multiple myeloma found that a single high dose of cyclophosphamide (2400 mg/m2) was more toxic and did not improve treatment response compared to standard dosing over four days.

Adding vincristine (1.4 mg/m2) at a specific time after cyclophosphamide did not enhance the treatment's effectiveness, showing no significant differences in response rates or survival between the treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma. Lenhard, RE., Kalish, LA., Oken, MM., et al.[2019]

References

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Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). [2015]

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[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. [2015]

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

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. [2014]

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

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. [2023]

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

Metabolism and disposition of dasatinib after oral administration to humans. [2015]

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

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. [2023]

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

Treatment of metastatic malignant melanoma with a combination of 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (NSC-45388), cyclophosphamide (NSC-26271), and vincristine (NSC-67574). [2020]

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Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma. [2019]

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Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group. [2018]

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Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation. [2019]