Cyclophosphamide + Sirolimus for Advanced Thyroid Cancer

Overseen By Paul Swiecicki

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: CYP3A4 inhibitors, P-glycoprotein inducers

Disqualifiers: GI impairment, Uncontrolled disorders, 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: 2

Duration: Up to 2 years

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two medicines, Cyclophosphamide (a chemotherapy drug) and Sirolimus (an immunosuppressant), to determine their effectiveness in treating advanced thyroid cancer that has spread and cannot be cured by standard treatments. Researchers aim to discover if this treatment can slow the cancer and assess its safety for patients. Individuals diagnosed with advanced thyroid cancer that has progressed despite treatment and who are unable or unwilling to undergo curative treatment might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong inhibitors or inducers of CYP3A4 or P-glycoprotein at least one week before starting the study medications. If you are on these types of medications, you will need to discontinue them.

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

Research has shown that the combination of Cyclophosphamide and Sirolimus is generally well-tolerated. Previous studies found that patients had similar rates of remaining free from disease progression, suggesting the treatment causes few severe side effects. While some risks exist, as with many cancer treatments, evidence indicates that patients usually manage this combination well. Prospective trial participants may find this information reassuring regarding the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for thyroid cancer?

Researchers are excited about the combination of Cyclophosphamide and Sirolimus for advanced thyroid cancer because it offers a novel approach compared to standard treatments like surgery, radioactive iodine, and targeted therapies. Cyclophosphamide is a chemotherapy agent that disrupts cancer cell DNA, while Sirolimus is an mTOR inhibitor that interferes with cell growth and division. This combination targets the cancer through dual mechanisms, potentially enhancing effectiveness and overcoming resistance seen in traditional treatments. By combining these two agents, there is hope for improved outcomes in patients with advanced cases of this challenging condition.

What evidence suggests that Cyclophosphamide and Sirolimus might be an effective treatment for advanced thyroid cancer?

Research has shown that using cyclophosphamide and sirolimus together might help treat advanced thyroid cancer. In one study, about 45% of patients did not experience cancer progression for a year after treatment. This suggests that the combination could effectively slow the disease. Most patients tolerated the treatment well, experiencing no severe side effects. While these results are promising, further research is needed to confirm them. ^{1 4 5 6 7}

Who Is on the Research Team?

Paul Swiecicki

Principal Investigator

University of Michigan Rogel Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced thyroid cancer that's spread and doesn't respond to radioactive iodine treatment. They should be able to perform daily activities (ECOG 0-2), not have had certain treatments recently, and must agree to follow the study plan. Pregnant or breastfeeding women, those unable to use contraception, and individuals with specific health issues or sensitivities to the drugs tested are excluded.

Inclusion Criteria

My thyroid cancer cannot be cured by surgery or I have chosen not to undergo curative treatment.

My cancer has grown despite treatment, and I have a tumor larger than 10 mm.

My organs and bone marrow are working well.

Exclusion Criteria

People who are in jail or prison.

Prior experimental therapy within 4 weeks of planned start of this trial

I do not have any serious health issues or infections that would stop me from receiving the study treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Sirolimus 4 mg, PO, days 1-28 and Cyclophosphamide 100 mg, PO, days 1-5 and 15-19 in 28-day cycles

Up to 2 years

Imaging every 2 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Toxicity Monitoring

Participants are monitored for toxicity up to 30 days after the last dose of study drug

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Sirolimus

Trial Overview The trial tests Cyclophosphamide and Sirolimus in patients with metastatic differentiated thyroid cancer. It's a non-randomized pilot study where participants take Sirolimus daily for 28 days and Cyclophosphamide on specified days within this cycle. The effectiveness is checked every two cycles through imaging.

How Is the Trial Designed?

Group I: Cyclophosphamide and Sirolimus Experimental Treatment 2 Interventions

Sirolimus 4 mg, PO, days 1-28 as well as Cyclophosphamide 100 mg, PO, days 1-5 and 15-19

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?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Published Research Related to This Trial

Adriamycin and bleomycin have shown definite activity against advanced thyroid carcinoma, making them the most studied agents for this condition.

Many other single agents and drug combinations were reviewed, but due to low patient enrollment in studies, meaningful statistical analysis was not possible; ongoing cooperative group protocols aim to improve patient accrual for better insights.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of chemotherapy in the treatment of advanced carcinoma of the thyroid gland. Poster, DS., Bruno, S., Penta, J., et al.[2004]

In a study of 11 patients with metastatic thyroid cancer treated with a combination of chemotherapy drugs, 6 patients showed a response, including one complete response that has lasted over 60 months.

While most responses were short-lived (2-3 months), the treatment was associated with moderate toxicity, primarily affecting blood cell counts, indicating that while chemotherapy can be effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy of metastatic thyroid cancer. Phase II study. Bukowski, RM., Brown, L., Weick, JK., et al.[2022]

Doxorubicin is currently the most effective chemotherapy for metastatic differentiated thyroid carcinoma, but it has limited effectiveness with rare complete responses and significant toxicity.

Newer agents like pemetrexed may offer better tolerance and potential benefits, highlighting the need for improved trial designs and patient recruitment to enhance treatment options for thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic chemotherapy for differentiated thyroid carcinoma. Sherman, SI.[2022]

The CHOP chemotherapy regimen used for treating post-transplant lymphoproliferative disease (PTLD) is associated with significant long-term health risks, including cardiac toxicity, hormone deficiencies, secondary leukemia, and osteonecrosis, affecting a high percentage of pediatric patients.

There is a dose-dependent increase in the risk of these long-term consequences, highlighting the urgent need for safer and more effective treatment options for PTLD that minimize these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of the risks of long-term consequences associated with components of the CHOP chemotherapy regimen. Watson, C., Gadikota, H., Barlev, A., et al.[2022]

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]

The combination of sirolimus and cyclophosphamide showed a one-year progression-free survival rate of 45% in patients with advanced differentiated thyroid cancers, which is higher than the 30% rate in the standard care comparison group, suggesting it may be a promising treatment option.

Patients receiving the sirolimus and cyclophosphamide combination experienced fewer average toxicities (0.87) compared to those on standard care (1.71), indicating that this treatment may be better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Study of Sirolimus and Cyclophosphamide in Patients with Advanced Differentiated Thyroid Cancers. Manohar, PM., Beesley, LJ., Taylor, JM., et al.[2020]

In a phase 2 study involving 36 patients with radioactive iodine-refractory thyroid carcinoma, the combination of sorafenib and temsirolimus resulted in a partial response rate of 22%, indicating improved efficacy compared to sorafenib alone, which had a response rate of only 12.2%.

The combination treatment showed a progression-free survival rate of 30.5% at one year, particularly benefiting patients who had not received prior systemic treatments, suggesting that this regimen could be a promising option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Sherman, EJ., Dunn, LA., Ho, AL., et al.[2018]

In a study of 29 patients with advanced thyroid cancer, etoposide, carboplatin, and cis-platinum were found to be active treatments, with etoposide showing the highest response rate and one complete response observed.

Patients under 65 years and those with medullary carcinoma had better response rates, and overall mean survival was 11.9 months, with responders living significantly longer (19 months) compared to non-responders (5.4 months).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy for thyroid cancer. Hoskin, PJ., Harmer, C.[2019]

In a phase II study involving 15 patients with non-Hodgkin's lymphoma (NHL) who had previously failed chemotherapy, the DHAOx regimen (dexamethasone, high-dose ara-C, and oxaliplatin) resulted in a 53% complete response rate, indicating its potential efficacy as a salvage treatment.

DHAOx demonstrated a favorable safety profile, with no increase in serum creatinine levels, suggesting low renal toxicity, and manageable side effects like myelosuppression and transient sensory peripheral neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin's lymphoma. Machover, D., Delmas-Marsalet, B., Misra, SC., et al.[2020]

In a study of 49 patients with metastatic nonanaplastic thyroid carcinoma treated over 10 years, only 3% showed any objective response to five different chemotherapy protocols, indicating very low efficacy of these treatments.

The disappointing results suggest a need for further research, specifically Phase II trials with new chemotherapeutic agents for this type of cancer, to explore potentially more effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy. Droz, JP., Schlumberger, M., Rougier, P., et al.[2022]

Well-differentiated thyroid carcinoma can be effectively treated with surgery and thyroid hormone therapy, often combined with radioiodine therapy, while some patients with more aggressive forms may benefit from chemotherapy.

Doxorubicin has shown effectiveness in treating thyroid carcinoma, but multiple-agent chemotherapy has only slightly better response rates than doxorubicin alone, highlighting the need for a collaborative approach in evaluating treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive management of thyroid cancer: chemotherapy. Shimaoka, K.[2019]

In the Euro-EWING99-R1 trial, cyclophosphamide was found to be as effective as ifosfamide for treating standard-risk Ewing sarcoma, with similar 10-year event-free survival rates of 93% for VAC and 95% for VAI.

However, patients treated with ifosfamide (VAI) experienced significantly higher kidney toxicity (43.0% vs 25.7% for VAC), highlighting the need to manage cumulative doses of alkylating agents to reduce long-term side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France. Corvest, V., Marec-Bérard, P., Lervat, C., et al.[2023]

The hyper-CVAD regimen, which includes cyclophosphamide, vincristine, doxorubicin, and dexamethasone, has shown significant effectiveness in treating adult lymphocytic leukemia and other blood cancers, such as Burkitt's disease and multiple myeloma.

Clinical trials conducted at the University of Texas M. D. Anderson Cancer Center have provided strong evidence for the efficacy of hyper-CVAD, leading to ongoing discussions about strategies to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The hyper-CVAD regimen in adult acute lymphocytic leukemia. Garcia-Manero, G., Kantarjian, HM.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4831630/

Retrospective Study of Sirolimus and Cyclophosphamide ... The one-year progression free survival rate (PFS) was 0.45, 95% CI [0.26, 0.80] in the sirolimus+cyp population and 0.30, 95% CI [0.13, 0.67] in the comparison ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27088062/

Retrospective Study of Sirolimus and Cyclophosphamide ... Conclusions: The combination of sirolimus and cyclophosphamide was generally well tolerated with similar progression free survival, highlighting its ...

3. withpower.com withpower.com/trial/phase-3-thyroid-diseases-3-2017-da7f0

Cyclophosphamide + Sirolimus for Advanced Thyroid Cancer The combination of sirolimus and cyclophosphamide showed a one-year progression-free survival rate of 45% in patients with advanced differentiated thyroid ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2017-00759

Cyclophosphamide and Sirolimus and in Treating Patients ... This phase II trial studies how well cyclophosphamide and sirolimus work in treating patients with thyroid cancer that has spread to other places in the body.

5. longdom.org longdom.org/open-access/retrospective-study-of-sirolimus-and-cyclophosphamide-in-patients-withadvanced-differentiated-thyroid-cancers-2167-7948-1000188.pdf

Retrospective Study of Sirolimus and Cyclophosphamide ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03099356

NCT03099356 | Cyclophosphamide and Sirolimus for the ... This study will be a non-randomized pilot trial using Cyclophosphamide and Sirolimus for the treatment of metastatic differentiated thyroid cancer. Patients ...

7. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/sirolimus?pn=1

Clinical Trials Using Sirolimus - NCI Cyclophosphamide and Sirolimus and in Treating Patients with Metastatic, Radioiodine-Refractory Thyroid Cancer. Status: Active. Location: University of ...