GAITHERSBURG, Md--By a unanimous vote, the FDA's Oncologic Drugs Advisory Committee (ODAC) recommended accelerated approval of Pharmacia & Upjohn's Camptosar (irinotecan hydrochloride injection), and the FDA responded by giving its ok to the drug 28 hours later.
GAITHERSBURG, Md--By a unanimous vote, the FDA's Oncologic DrugsAdvisory Committee (ODAC) recommended accelerated approval ofPharmacia & Upjohn's Camptosar (irinotecan hydrochloride injection),and the FDA responded by giving its ok to the drug 28 hours later.
Camptosar, the first new agent approved for colon cancer in 40years, is indicated for metastatic carcinoma of the colon or rectumthat has recurred or progressed following fluorouracil (5-FU)-basedtherapy.
Camptosar, also known as CPT-11, is converted in the body to SN-38,a potent modifier of topoisomerase I, an enzyme responsible forDNA incision and relaxation prior to cell replication. SN-38 stabilizesthe enzyme with DNA and this "leads to a double-strandedDNA break that results in cell death," explained LangdonMiller, MD, of Pharmacia & Upjohn. "In essence, SN-38converts topoisomerase I into a cellular toxin."
Daniel D. Von Hoff, MD, of the University of Texas Health ScienceCenter, San Antonio, noted that physicians in the United Stateswill diagnose more than 133,000 colorectal cancers and the diseasewill kill 54,000 people in 1996. Only about 12% of patients whoseinitial tumor metastasizes live more than 2 years.
"There has been no effective single-agent therapy for patientswith advanced colorectal cancer after they have received priortreatment with 5-FU or a 5-FU containing regime," Dr. VonHoff said.
Henry C. Pitot, MD, of the Mayo Clinic, reviewed three pivotalCamptosar trials with a total of 304 previously treated colorectalpatients. (Upjohn began a phase III study in May 1996). "Theefficacy endpoint was objective complete or partial tumor response,"he said.
Thirty-nine patients (12.8%) responded, 2 with a complete responseand 37 with partial responses, Dr. Pitot said. "Nearly 40%to 65% of patients had stable disease as their best response,with some patients experiencing substantial or protracted reductionin tumor burden," he added. Time to progression was about6 months for those with stable disease and median survival was9 months with a range of up to nearly 3 years.
Dr. Pitot also cited results from two foreign studies. In France,15.6% of 147 colorectal patients treated with CPT-11 responded,and in Japan, the response rate was 21.7% among 46 patients.
In the three US-based trials, diarrhea, nausea, and neutropeniawere regarded as the most important clinical toxicities seen in10% or more of the patients, said Mace L. Rothenberg, MD, of theUT Health Science Center, San Antonio.
Patients experienced two types of diarrhea. One, a cholinergicreaction, struck shortly after drug infusion. The other, diarrheathat occurs several days later, is the most common moderate tosevere toxicity of CPT-11 and lasts a median of 2 days, Dr. Rothenbergsaid.
Only 1.3% of patients discontinued Camptosar because of diarrhea,he said, and there were no deaths attributable to this late toxicity.Grade 3 vomiting affected 9.9% of patients and grade 4 vomitinghit 2.6%, but this could be controlled. Grade 3 or 4 neutropeniaoccurred infrequently in CPT-11 patients, 14.8% and 11.5%, respectively.
Neutropenic fever occurred in 3% of patients, Dr. Rothenberg said,and "only one patient died as a consequence of neutropenicsepsis." However, Dr. Isagani Chico of the FDA told ODACthat his independent analysis suggested that five deaths thatoccurred in the trials "were probably or possibly relatedto CPT-11."
Summing up, Dr. Miller told the FDA panel that the three studiesdemonstrate "that CPT-11, when given in repeated coursesbeginning at a starting dose of 125 mg/m² weekly for 4 weeks,followed by a 2-week rest, has consistent activity and manageabletoxicity in the therapy of patients with previously treated colo-rectalcancer."
The advisory panel voted 8-to-1 that the three phase II studieswere adequate and well-controlled for the primary endpoint oftumor shrinkage. The panel then agreed unanimously that the overallobjective response rate of 12.8% in the three studies (0.7% complete;12.2 partial), with a median duration of 6 months, was sufficientevidence of Camptosar's antitumor activity in patients previouslytreated for colorectal cancer.
The committee then unanimously agreed that the late diarrhea andneu-tropenia, and the hospitalization of more than one quarterof patients because of drug-related adverse effects, were acceptabletoxicity for patients with refractory colorectal cancer.
The panel decided not to vote on the question of whether the 12.8%response rate and the overall toxicity profile seen in the studiesconstituted sufficient evidence for a net patient benefit. Instead,they voted 9-to-0 to recommend that the FDA approve Camptosarfor colorectal cancer patients with disease that has recurredor progressed after treatment with fluorouracil.