Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

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Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.01.149 ◽

2005 ◽

Vol 23 (28) ◽

pp. 7199-7206 ◽

Cited By ~ 246

Author(s):

Lawrence V. Rubinstein ◽

Edward L. Korn ◽

Boris Freidlin ◽

Sally Hunsberger ◽

S. Percy Ivy ◽

...

Keyword(s):

Phase Ii ◽

False Positive ◽

Standard Treatment ◽

False Negative ◽

Error Rates ◽

Targeted Treatment ◽

Phase Iii ◽

Phase Ii Trials ◽

Treatment Control ◽

Randomized Phase Ii

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing “phase II screening trials,” in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates (α or type I error) and false-negative error rates (β or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

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Trends in Phase II Trials for Cancer Therapies

Cancers ◽

10.3390/cancers13020178 ◽

2021 ◽

Vol 13 (2) ◽

pp. 178

Author(s):

Faruque Azam ◽

Alexei Vazquez

Keyword(s):

Phase Ii ◽

Null Model ◽

Surrogate Endpoint ◽

Response Rates ◽

Drug Combinations ◽

Phase Iii ◽

Cancer Drug ◽

Cancer Therapies ◽

Targeted Agents ◽

Phase Ii Trials

Background: Drug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase. Methods: We analysed recent Phase II cancer trials comprising 2165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy. Results: Targeted therapies reach higher response rates when used in combination with cytotoxic drugs. We identify four synergistic and 10 antagonistic combinations based on the observed and expected response rates. We demonstrate that recent targeted agents have not significantly increased the response rates. Conclusions: We conclude that either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.

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