Marcel Rozencweig

Multinational, Double-Blind, Phase III Study of Prednisone and Either Satraplatin or Placebo in Patients With Castrate-Refractory Prostate Cancer Progressing After Prior Chemotherapy: The SPARC Trial

PURPOSEnThis multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen.nnnPATIENTS AND METHODSnNine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m(2) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP).nnnRESULTSnA 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin.nnnCONCLUSIONnOral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

Phase II study of 9-hydroxy-2N-methylellipticinium acetate

A broad phase II trial of elliptinium was conducted in 105 evaluable patients with advanced solid tumors. The drug was given as a 60-90-min i.v. infusion at a weekly dose of 100 mg/m2. Of 36 breast cancer patients, one achieved complete and six achieved partial response for an overall response rate of 19%. Responses lasted for 12-56 weeks from initiation of therapy. There was also one partial response among 21 patients with squamous cell carcinoma of the lung. No response could be obtained in 17 patients with colon cancer, 13 patients with head and neck cancer and 18 patients with a wide variety of other malignancies. Myelosuppression was minimal. Nausea and vomiting were the most frequent toxic effects. The drug also produced serious xerostomia and acute intravascular hemolysis. Asthenia was common. Other adverse reactions included fever and chills, transient neurologic and cardiovascular manifestations and renal function impairment. Additional work is needed to define optimal modes of drug administration.

Phase II trial of epirubicin in advanced squamous, adeno- and large cell carcinoma of the lung

Epirubicin , a stereoisomer of doxorubicin with suggested lower potential for cardiotoxicity in animal tumor systems, was evaluated in a disease-oriented phase II trial in non-small cell lung cancer. The drug was given as a direct i.v. injection of 90 mg/m2 repeated every 3 weeks. Four partial remissions were observed among 75 evaluable patients. Forty-two of the 75 patients had received no prior chemotherapy. The predicted true response rate is equal to 5% (0.2-10%). Leucopenia (75% of patients), gastrointestinal disturbances (76% of patients) and alopecia (53% of patients) were common side-effects observed. Four patients had cardiac abnormalities after treatment with epirubicin (one sinustachycardia , two premature beats, one biopsy-proven cardiomyopathy with congestive heart failure). One patient developed a peripheral neuropathy possibly related to epirubicin . We conclude that epirubicin in the present dose and schedule is an inactive agent in patients with non-small cell lung cancer.

Phase II study of oral VP-16-213 in hepatocellular carcinoma

In a disease-oriented phase II study, 26 patients with hepatocellular carcinoma were treated with oral VP-16-213 at 120 mg/m2/day for 5 consecutive days, repeated every 3 weeks. Of 24 evaluable patients, 3 achieved partial remission (PR) for 12, 16 and 35 weeks respectively. Minor regression or stabilization of the disease (NC) was achieved in 8 patients for a median duration of15 weeks. Patients with PR and NC experienced similar median survival (22 weeks), whereas non-responders had a median survival of less than8 weeks. Results of this trial indicate that VP-16-213 has limited but definite anti-tumor activity in hepatocellular carcinoma.

Epirubicin in colorectal cancer - A phase II study of the early clinical trials group (EORTC)

SummaryEpirubicin, a stereoisomer of doxorubicin with suggested lower potential for cardiotoxicity in experimental animal tumor systems, was studied in a disease-oriented phase II trial in patients with advanced colorectal cancer. The drug was given as a direct iv injection of 90 mg/m2 q 3 weeks. No objective response was observed in 52 evaluable patients with colon (n = 34) and rectal (n = 18) carcinoma. Fourteen patients (27%) had stable disease for a median of four treatment courses. Leukopenia (88%), nausea and vomiting (71%) and alopecia (54%) were the most common toxic effects.We conclude that epirubicin at the present dose and schedule is an ineffective agent in patients with metastatic colorectal cancer.

Randomized phase II trial of carminomycin versus 4'-epidoxorubicin in advanced breast cancer.

Sixty-three evaluable patients with advanced breast cancer were randomly allocated to receive three-week intravenous courses of carminomycin (18 mg/m2) or 4-epidoxorubicin (90 mg/m2). The former yielded one (3%) partial response for nine weeks among 29 patients whereas, in the other arm, nine (27%) of 34 patients achieved partial response for a median of 28 weeks (range, nine to 36 weeks; p less than 0.02). The major toxic effect of these anthracyclines was leukopenia with median white blood cell nadirs of 1,600/microL (range, 300-4,000/microL) versus 1,800/microL (range, 500-4,300/microL), respectively. Acute nonhematologic toxic effects were qualitatively similar but carminomycin produced significantly less gastrointestinal intolerance and alopecia. Patients whose disease failed to respond to first-line anthracycline received doxorubicin (60 mg/m2) every three weeks. Four partial responses were obtained among 19 patients previously treated with carminomycin. Following 4-epidoxorubicin therapy, one of 12 evaluable patients also attained partial response. Survival curves were not affected by the initial treatment option. Carminomycin has marginal activity against breast cancer whereas 4-epidoxorubicin deserves further evaluation of its therapeutic index relative to doxorubicin. The design used in this trial appears attractive for prompt phase II evaluation of anthracycline analogs.

Phase II study of 5' deoxy 5 fluorouridine (doxifluridine) in advanced malignant melanoma

SummaryForty-two patients with malignant melanoma were treated with doxifluridine, 4000 mg/m2 daily ×5, repeated every 3 weeks. The daily dose was reduced to 3000 mg/m2 in patients who had experienced severe myelosuppression with prior chemotherapy. A total of 35 patients were evaluable for response, and 25 of these received two or more courses. Two responses were observed. Toxicity mainly took the form of nausea, vomiting, stomatitis, dizziness, ataxia, and fatigue. Mild leukopenia was frequent (43%). Nadir counts <1.5×109/l leukocytes or 50×109/l platelets were seen in 7% and 2% of the courses respectively. Doxifluridine has no useful activity against malignant melanoma.

Phase II study of amsacrine in solid tumors: a report of the EORTC Early Clinical Trial-Group.

A total of 239 patients with advanced solid tumors were treated in this phase II trial. Amsacrine was administered as a single i.v. dose of 120 mg/m2 repeated at 21-day intervals. The initial dose was reduced to 90 mg/m2 in the case of extensive prior therapy. Some antitumor activity was detected in head and neck cancer but the drug appears to lack significant efficacy in epidermoid lung cancer as well as in carcinoma of the breast, melanoma, renal cell cancer, colorectal cancer and non-seminomatous testicular cancer. Leukopenia was the major toxic effect encountered in this trial and was similar at 90 and 120 mg/m2.

Phase II trial of diaziquone (AZQ) in advanced malignant melanoma

Forty-two evaluable patients with malignant melanoma received AZQ 27 mg/m2 i.v. every 4 weeks. In 5 patients with poor marrow reserve this dose was reduced to 20 mg/m2. Doses were rapidly escalated when no significant myelosuppression was encountered in previous courses. Twenty-five patients had received no prior chemotherapy. A single partial response was obtained for 3 months. Inconsistent myelosuppression was the main toxic effect in this trial. The median WBC and platelet nadirs were 3200/mm3 (900-19,500) and 105,000/mm3 (33,000-530,000) respectively. In 2 patients leukopenia was complicated by a transient episode of infection. One-third of the patients did not experience significant myelosuppression. Non-hematologic adverse reactions were generally mild to moderate and consisted of nausea and vomiting in 26 patients and alopecia in 1. It is concluded that at this dose schedule AZQ is ineffective against malignant melanoma.