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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and observe the side effects of combining three drugs—dasatinib, temsirolimus, and cyclophosphamide—to treat advanced solid tumors that have spread, returned, or resisted previous treatments. Dasatinib and temsirolimus block enzymes necessary for tumor growth, while cyclophosphamide prevents tumor cells from growing and spreading. This study may suit those with a solid tumor that has not improved with standard treatments and continues to grow. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

A previous study found that the combination of dasatinib, temsirolimus, and cyclophosphamide was generally safe and well-tolerated. While some treatment-related side effects occurred, they mostly appeared early and were manageable, allowing most patients to continue treatment.

This combination is being tested to determine the optimal dose that balances efficacy and safety. As this is an early-phase trial, the primary focus is on understanding the side effects and patient tolerance. The individual drugs in this combination have been used for other conditions, providing a safety profile. However, using them together is new, making this trial crucial for understanding their combined effect in treating cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination because it targets cancer using a multi-faceted approach. Unlike traditional chemotherapy that broadly attacks rapidly dividing cells, dasatinib is a kinase inhibitor that specifically targets proteins involved in cancer cell growth. Temsirolimus, another component, inhibits mTOR, a pathway crucial for cancer cell survival and proliferation. The addition of cyclophosphamide, a well-known chemotherapy agent, helps to further enhance the treatment's effectiveness. This combination aims to provide a more targeted attack on cancer cells, potentially leading to improved outcomes with fewer side effects than conventional treatments.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research has shown that dasatinib and temsirolimus can block enzymes that aid cancer cell growth, potentially slowing or stopping the progression of certain cancers. Cyclophosphamide, a chemotherapy drug, kills cancer cells or prevents them from dividing. In this trial, participants will receive a combination of dasatinib, temsirolimus, and cyclophosphamide. Some studies have found dasatinib effective in treating certain advanced solid tumors, while temsirolimus has shown promise in shrinking tumors. Combining these drugs might enhance their effectiveness against tumors that have spread or are resistant to other treatments. Early results suggest this combination could be a strong option for treating advanced cancers. ^{1 2 4 5 6}

Who Is on the Research Team?

Wafik T Zaky

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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