What is the mechanism of action of this treatment?

Cyclophosphamide and Sirolimus are two treatments for Medullary Thyroid Cancer (MTC) that work through distinct mechanisms. Cyclophosphamide is a cytotoxic agent that alkylates DNA, causing DNA cross-linking and cell death, which is effective against rapidly dividing cancer cells. Sirolimus inhibits the mTOR signaling pathway, crucial for cell growth and proliferation, thereby slowing or stopping cancer cell growth. These mechanisms are vital for MTC patients as they provide alternative strategies to control tumor progression, especially when other treatments fail.

What side effects are associated with this type of intervention?

Common treatments for Medullary Thyroid Cancer (MTC) include kinase inhibitors and cytotoxic agents. Kinase inhibitors, such as those targeting the RET kinase, can cause side effects like hypertension, diarrhea, and fatigue. Cytotoxic agents, including Cyclophosphamide, can lead to nausea, vomiting, bone marrow suppression, and increased risk of infections. Sirolimus, an mTOR inhibitor, is associated with side effects such as mouth ulcers, infections, hyperlipidemia, and delayed wound healing. These treatments aim to manage advanced MTC but come with significant potential side effects that need to be monitored closely.

What prior FDA approvals exist?

The FDA has approved several treatments for Medullary Thyroid Cancer (MTC), including vandetanib and cabozantinib, which are tyrosine kinase inhibitors. These drugs work differently from Cyclophosphamide, which is a DNA-alkylating agent, and Sirolimus, which is an mTOR inhibitor. While there are no direct FDA-approved treatments for MTC that use DNA alkylation or mTOR inhibition, the ongoing trial of Cyclophosphamide and Sirolimus represents an exploration of these mechanisms in treating metastatic, RAI-refractory, differentiated thyroid cancer.

What other types of research exist?

Promising novel alternatives for Medullary Thyroid Cancer patients include selective RET inhibitors such as selpercatinib and pralsetinib, which target RET mutations commonly found in MTC. Additionally, antiangiogenic multikinase inhibitors like vandetanib and cabozantinib have shown efficacy in treating MTC by stabilizing disease progression.

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Alkylating agents

Cyclophosphamide + Sirolimus for Advanced Thyroid Cancer

Phase 2

Recruiting

Led By Paul Swiecicki, M.D.

Research Sponsored by University of Michigan Rogel Cancer Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Histologically documented differentiated thyroid cancer with or without metastases, not amenable to curative treatment; or the patient has documented refusal of curative treatment

Measurable disease (>10 mm) and have progression of disease based on RECIST criteria. Previously irradiated tumor lesions are not considered measurable unless they have progressed since radiation.

Must not have

A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment

Patients with known sensitivities to either cyclophosphamide and/or sirolimus

Timeline

Screening 3 weeks

Treatment Varies

Follow Up patients will be followed until death or up to 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial uses two drugs, Cyclophosphamide and Sirolimus, to treat patients with thyroid cancer that has spread. Cyclophosphamide kills cancer cells by breaking their DNA, while Sirolimus stops them from growing. Sirolimus has been used in various treatments and has shown effectiveness against different cancers. Patients are monitored for side effects and effectiveness.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include immune system suppression leading to increased infection risk, nausea, vomiting, mouth sores from Cyclophosphamide; and mouth ulcers, high cholesterol levels, lung problems from Sirolimus. Side effects can vary based on individual patient conditions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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

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I am able to get out of my bed or chair and move around.

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Iodine-131 treatment did not work for me or I can't receive it.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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I am allergic to cyclophosphamide or sirolimus.

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I have a blockage in my urinary tract.

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I am mentally capable of understanding and following the study's requirements.

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I have been treated with an mTOR inhibitor before.

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I haven't had advanced genetic testing on my cancer.

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My stomach or intestines do not work well, affecting how I absorb medicine.

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I am not using, or unable to use, birth control or practice abstinence.

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I am not pregnant or breast-feeding.

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I have not had 131I therapy in the last 6 months, or 1 month if my post-treatment scan was negative.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ patients will be followed until death or up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~patients will be followed until death or up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and patients will be followed until death or up to 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Percentage of patients that respond to treatment

Secondary study objectives

Median overall survival time

Median progression free survival time

The number of patients that experience toxicity

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Cyclophosphamide and SirolimusExperimental Treatment2 Interventions

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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Sirolimus

2013

Completed Phase 4

~2750

Cyclophosphamide

2010

Completed Phase 4

~2310

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Cyclophosphamide and Sirolimus are two treatments for Medullary Thyroid Cancer (MTC) that work through distinct mechanisms. Cyclophosphamide is a cytotoxic agent that alkylates DNA, causing DNA cross-linking and cell death, which is effective against rapidly dividing cancer cells. Sirolimus inhibits the mTOR signaling pathway, crucial for cell growth and proliferation, thereby slowing or stopping cancer cell growth. These mechanisms are vital for MTC patients as they provide alternative strategies to control tumor progression, especially when other treatments fail.

Autophagic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer.Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors.Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models.