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Cyclophosphamide and Sirolimus and in Treating Patients with Metastatic, Radioiodine-Refractory Thyroid Cancer

Trial Status: Active

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 and does not respond to treatment with radioiodine. 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. Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide and sirolimus may work better in treating patients with thyroid cancer.

Inclusion Criteria

  • 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
  • Previous failure of iodine-131 (131I) therapy or not candidates to receive 131I as assessed by treating physician
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Life expectance of >= 12 weeks
  • 131I therapy not allowed within 24 weeks before entry (4 weeks if negative post-treatment scan)
  • White blood cells (WBC) >= 3 x 10^9 cells/mL
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9 cells/mL
  • Hemoglobin >= 9 g/dL
  • Platelets >= 75,000 cells/mm^3
  • Prothrombin time (PT) < 1.5
  • Total serum bilirubin within 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) within 2.5 x ULN unless there are liver metastases in which case, AST within 5 x ULN
  • Alanine aminotransferase (ALT) within 2.5 x ULN unless there are liver metastases in which case, ALT within 5 x ULN
  • Serum creatinine clearance >= 30 mL/min
  • Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment; women not of child-bearing potential will be defined as all women older than age 50 and anovulatory for 12 months
  • Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment
  • Willingness and ability to comply with scheduled visits, treatment plans, including willingness to take study medication, laboratory tests, and other study procedures

Exclusion Criteria

  • Inability to obtain Foundation One testing on archival tissue, or, lack of previous next generation sequencing
  • Chemotherapy, tyrosine kinase inhibitor, or radiation therapy within 4 weeks
  • Prior experimental therapy within 4 weeks of planned start of this trial
  • 131I therapy within 24 weeks before entry (4 weeks if negative post-treatment scan)
  • Previous treatment with an mTOR inhibitor
  • Patients who are currently receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with cyclophosphamide and sirolimus: * Strong inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp)
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study medications (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection) including dependence on a gastrostomy (G)-tube for administration of medications
  • 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
  • Patients with known urinary outflow obstruction
  • Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol
  • Patients (male and female) having procreative potential who are not willing or not able to use adequate contraception or practicing abstinence
  • Women who are pregnant or breast-feeding
  • Patients residing in prison


Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Francis Paul Worden
Phone: 734-615-6633


I. To assess any preliminary evidence of anti-tumor activity by assessment of objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 in patients with metastatic differentiated thyroid cancer treated with cyclophosphamide and sirolimus.


I. To describe the adverse events associated with use of cyclophosphamide and sirolimus.

II. To assess survival in patients with metastatic differentiated thyroid cancer treated with cyclophosphamide and sirolimus.


I. To explore the response to therapy based on tumor genotype, specifically BRAF mutation status, as identified by next generation sequencing (i.e. Foundation One).

II. To explore health related quality of life compared to historical control, specifically as assessed by Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) questionnaire.

III. To explore whether radiographic response to therapy correlates with serum thyroglobulin response.


Patients receive sirolimus orally (PO) once daily (QD) on days 1-28 and cyclophosphamide PO on days 1-5 and 15-19. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days and then every 3 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Francis Paul Worden

  • Primary ID UMCC 2017.013
  • Secondary IDs NCI-2017-00759, HUM00126559
  • ID NCT03099356