Rhodamine-123 Clinical Trial

Phase I toxicity study for an innovative treatment for hormone-refractory prostate cancer.  The Phase I clinical trial consists of a single dose toxicity study and a multidose toxicity study:

Single Dose Toxicity Study

The purpose of the single dose toxicity study was to determine a safe dosing level for Rhodamine-123.  It was completed in March 2001.  The following abstract summarizes the study.

Rhodamine-123: Innovative Treatment for Prostate Cancer

Introduction and Objective: There is no life prolonging treatment for hormone-refractory prostate cancer. Basic research in innovative chemotherapy is therefore urgently needed. Rhodamine-123 (Rh-123) is a cationic, lipophilic, water-soluble oxonium chloride salt with a high affinity for the mitochondria of malignant cells. Rh-123 has been found to be selectively toxic to a number of human cancer cell lines including three derived from the prostate. Prostate cancer induced in animals has also been found to be affected by Rh-123. The lethal dose for animals (LD10) is approximately 20 mg/kg body weight. The objective of this study was to determine safe dosage levels of Rh-123 for humans.

Methods: An FDA Investigational New Drug Phase I application was filed and approved (IND 56,539). Nineteen volunteers with hormone-refractory prostate cancer and a rising prostate specific antigen (PSA) on 3 (or more) occasions received a single 15-minute intravenous infusion of Rh-123. The dose levels of 12, 24, 48, 96 and 134 mg/M2 of body surface area were chosen because they bracketed the LD10 determined in our pre-clinical animal studies. Study parameters included history, physical, Karnofsky performance score, a complete blood count, comprehensive metabolic profile, cardiac enzymes, PSA, acid phosphatase, serum magnesium and electrocardiogram.  Toxicity grading was based on the NCI Common Toxicity Criteria.

Results: Transient drops in PSA were observed. The first signs of toxicity were observed at the dose level of 134 mg/M2. The toxicities observed were three grade 1 (gastrointestinal, hematologic and cardiovascular), two grade 2 (hematologic), and two grade 3 (cardiovascular and neurologic).  These changes met our definition of dose limiting toxicity (DLT). All toxicities resolved within the first 24 to 96 hours following the infusion.

Conclusions: DLT followed a single infusion of 134 mg/M2 of Rh-123. Therefore, a dose of 96 mg/M2 is considered to be the maximum tolerated dose (MTD) for humans.

Multidose Toxicity Study

The purpose of the multidose toxicity study was to determine the safety of repeated doses of Rhodamine-123 at its safe dosing level as determined in the single dose toxicity study.  It was completed in December, 2003.

Rhodamine-123: A Phase I Study for Hormone-Refractory Prostate Cancer

Objective:  The objective of this study was to determine the safety of six doses of Rh-123 given at the maximum tolerated dose of 96 mg/M2 at 28-day intervals.

This study involved 10 volunteer participants with metastatic hormone-refractory prostate cancer.

Background: Rh-123 has been used in research laboratories to identify selected subpopulations of cells (flow cytometry). In 1982, it was proposed that Rh-123 might be selectively toxic to transformed cells by virtue of its selective uptake and retention in their mitochondria. In vivo animal experiments using transplantable and induced tumor systems showed evidence of anti-tumor activity. In vitro studies on three established prostate cancer derived cell lines, PC3, DU 145 and LNCaP, confirmed cell kill.

Eligibility Criteria: Participants must have been at least 3 weeks post major surgery and at least 4 weeks post prior XRT or chemotherapy. Karnofsky's score greater than or equal to 60 and a life expectancy of 180 days or more. Rising PSA determinations will have been done on three separate occasions with continuing hormone therapy, indicative of disease progression. Participants will have had either a bilateral orchiectomy or an LH/RH agonist and had disease progression despite these treatments.

Study Parameters: History, including quality of life instruments; physical; Karnofsky performance score; complete blood count; comprehensive metabolic profile; cardiac enzymes; prostate specific antigen (PSA); prostatic acid phosphatase; serum magnesium and electrocardiogram. An aliquot (serum blank) were retained for pharmacokinetic studies. Collection periods were 0-7 days before each infusion, 96 hours after each infusion, and six months and one year after the first infusion.

All patients must have had a consultation with Dr. Lawrence W. Jones prior to entry at the Huntington Medical Research Institutes. After the consultation, all patients had a pre-chemotherapy appointment with a co-investigator and an infusion room RN for clinical evaluation and education.

Administration Plan:  Six 30-minute IV infusions given 28 days apart.

Side effects: Unknown except for possible transient hypertension, appetite loss, loss of weight, and abnormal blood tests. Toxicity grading will be based on the NCI Common Toxicity Criteria.

For more information please contact:
Cecile Vergon or Jill Nuccio
Huntington Medical Research Institutes
Tel: (626) 397-5800
E-mail: jnuccioathmridotorg