Phase Ib/II Study of Phenoxodiol in Patients with Recurrent Ovarian, Fallopian and Primary Peritoneal Cancer that is Resistant to ≥ Second Line Chemotherapy
Thomas J. Rutherford, M.D., Ph.D; David M. O’Malley, M.D.; Anita Makkenchery, M.D.; Lisa Baker, B.S.N.; Masoud Azodi, M.D; Peter E. Schwartz, M.D.; Gil Mor, M.D., Ph.D.;
Yale University School of Medicine, Department of Obstetrics and Gynecology, New Haven, Connecticut

Abstract
Background
Objective
Methods
Results
Conclusions

Abstract

Introduction: Resistance to apoptosis is a critical step in cancer development and chemoresistance. Apoptosis-based tumor therapy represents a new and promising approach for the treatment of cancer. Recently we have shown that Phenoxodiol (PxD) selectively removes blockers of apoptosis in chemo resistant ovarian cancer cells and inhibits tumor growth in vivo. The objective of this study was to evaluate the toxicity and preliminary efficacy of PxD in recurrent ovarian cancer.

Methods: Forty patients with documented recurrence after second line chemotherapy and histologically confirmed epithelial ovarian, fallopian or primary peritoneal cancer were eligible for this study. Patients were randomized at four dose levels (1, 3, 10, 20 mg/kg), ten patients per dose, and received treatment consisting of bolus PxD weekly on two consecutive days. Toxicity was scored according to NCI criteria. Response was defined according to Recist criteria in patients with measurable disease or Rustin criteria in evaluable patients with CA125 criteria.


Structure of Phenoxodiol

Results: Forty patients (median age 56--range 21-78) were enrolled. The median number of prior chemotherapy regiments was 5 (range: 2 - 11). All the patients failed additional salvage therapies (3-11) including Doxil (17.5%), topotecan (30%), gemcitabine (17.5%), docetaxel (10%). No MTD was reached and no differences in safety were found between the four doses. One platinum/paclitaxel refractory patient was progression free for 36 weeks. Based on serological markers, six patients responded at six weeks of treatment (15%) (average 54% decrease in CA125) and ten patients had stable disease (25%). A mean of 12 weeks of therapy/patient were administrated with 15 patients receiving greater than 12 weeks (range 12-36).

The most common toxicities (Grade 1 and 2) were fatigue, depression, lightheadedness and headache. There was one treatment - related toxicity of Grade 3 thrombocytopenia and hypertension.

Eight of ten patients that were treated with a taxane following phenoxodiol treatment showed a marked serologic response to taxanes (64% decrease in CA125). Five of the ten patients were characterized as taxane-sensitive, and four of this five responded to taxol treatment. The other five patients were characterized as taxane resistant/refractory (previously had recurred while on taxane therapy or within six months of completion of therapy) and four of these patients responded to taxane therapy



Conclusion: Pre-clinical studies have shown Phenoxodiol as a potent regulator of apoptosis, acting as a chemo-sensitizer, with no toxic effect in normal cells. In the present study, we have confirmed the lack of major toxicity in patients with ovarian cancer and showed a serologic response in recurrent ovarian cancer patients. Phenoxodiol was found to be very well tolerated at the dose levels reported here in. In these heavily pre-treated patients, 25% stable disease was documented after six weeks and 10% stable disease after 12 weeks. In addition, an 80% response to taxol treatment was observed in patients that completed an average of 12 weeks phenoxodiol treatment. A study to evaluate Phenoxodiol in combination with cisplatin or paclitaxel in platinum refractory or resistant ovarian cancer patients is being investigated.

TOP

• Histological evidence of ovarian, fallopian or primary peritoneal carcinoma and disease
• Failure to at least second-line therapy
• Documented recurrent, progressive disease
• Estimated life-expectancy of at least 3 months.
• Laboratory evidence of normal renal, hepatic and bone marrow function

• Concurrent investigational drug study without active infection and without active CNS metastases.
• Patients with known CNS metastases must have received prior radiation therapy, and CNS metastatic disease must be stable for 4 weeks.
• Patients must have recovered from the acute effects of any prior anti-neoplastic therapy.
• Patients must not have had whole abdominal radiation

• Patients were treated at one of four dose levels (1, 3, 10, 20 mg/kg), ten patients per dose.
• Bolus infusion of Phenoxodiol was administered weekly on 2 consecutive days over 10-20 minutes.
• Treatment cycles were twelve weeks
• Toxicity was scored according to NCI criteria.
• Response was defined according to Recist criteria in patients with measurable disease or Rustin criteria in evaluable patients with CA125 criteria.