This is a dosage escalation study to estimate the maximum tolerated dose of 9-cis-retinoic
acid given in combination with tamoxifen. Groups of 3 to 6 patients receive oral
9-cis-retinoic acid daily for 4 weeks, after which daily oral tamoxifen is added to the
regimen. Patients continue treatment for up to 28 weeks, with tamoxifen continued after the
study if medically appropriate.
This is a Phase I study of the combination tamoxifen and 9-cis-Retinoic acid in patients
with breast cancer. The primary objective of the study is; 1) to determine the maximum
tolerated dose of 9-cis-Retinoic acid in combination with Tamoxifen and to determine the
overall and dose limiting toxicities. Other objectives are: 2) to determine the effect of
Tamoxifen on the pharmacokinetics of 9-cis-Retinoic acid; 3) to evaluate the anti-tumor
activity of this combination therapy within the context of a phase I study; 4) and to
determine the expression of surrogate biomarkers of breast carcinogenesis before and after
All patients must have histologically documented diagnosis of Stage III, or IV breast
Patients with stage III that has completed chemotherapy: Estrogen receptor (ER) or
progesterone receptor (PR) positive tumor required if premenopausal. Either
ER/PR-positive or -negative tumor allowed if postmenopausal and have received prior
Patients may have stage IV with ER/PR-positive or -negative tumor.
No CNS metastases, pseudotumor cereri, or seizures.
Patients who have ecovered from the toxic effects of prior therapy will be eligible.
Patients with prior tamoxifen will be allowed to participate. At least 3 weeks must have
elapsed since the last dose of chemotherapy.
Age: 18 and over.
Sex: Men and women.
Menopausal status: Any status.
Patients must have a performance status of ECOG 0-2.
Patients must have Hematopoietic criteria of:
ANC at least 1,500/mm(3).
Platelet count at least 90,000/mm(3).
Patients must have Hepatic criteria of:
In the absence of tumor involvement:
Bilirubin no greater than twice normal;
SGOT no greater than twice normal;
Alkaline phosphate no greater than twice normal;
Fasting triglycerides less than 3 times normal.
Patients must have Renal criteria of:
Serum creatinine no greater than 1.5 mg/dL OR;
Creatinine clearance at least 60 mL/min.
No allergy to study medications.
No nonmalignant systemic disease that would preclude therapy.
No second malignancy within 5 years except: Curatively treated basal cell skin carcinoma.
Cervical carcinoma in situ.
Pregnant women will be excluded.
Negative pregnancy test required within 7 days prior to entry.
Adequate contraception required for 4 weeks prior to, during, and for 1 year after study.
Patients must give informed consent.
Patients who are poor medical or psychiatric risks will be eligible.