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Background: The conventional phase I trial design yields an estimate of the maximum tolerated dose (MTD) of a new drug defined from treatment toxic effects observed in a small heterogenous cohort of patients. The MTD is specific for those patients treated in the study and may not be reproducible in another patient series, a limitation known as cohort dependency. Purpose: We conducted an opinion survey of phase I investigators in an attempt to characterize physician attitudes and clinical practices regarding assessment of risk of toxic effects in patients. Methods: A physician opinion survey of scaled multiple choice and open-ended questions was distributed to oncologists (faculty and fellows) at National Cancer Institute (NCI)-funded phase I contract institutions. The target sample was narrowed to these specific institutions because of their experience in conducting various phase I trials. Each NCI-funded phase I contractor received an instruction sheet and 25 surveys and envelopes that were made available to oncologists enrolling patients in phase I trials. Results: Of the 75 surveys distributed, 67 (89%) were returned. Most respondents agreed that unexplained variability in toxicity exists in phase I trials. However, opinion varied considerably among five participating institutions (two-sided P = .001). Informal scoring of patients for toxicity risk prior to treatment was a common practice (85% overall), although the prevalence of this practice varied somewhat among the institutions (two-sided P = .01). Physicians' opinions were mixed regarding the practice of becoming increasingly selective in enrolling patients as the MTD was approached, with strong disagreement noted among institutions (two-sided P = .001). Given background on a hypothetical phase I trial, respondents were asked to rank the usefulness of 27 patient factors for predicting the risk of dose-limiting leukopenia. Eight factors were perceived as strongly informative: Eastern Cooperative Oncology Group performance status of 2 or worse, recent weight loss of more than 10%, multiple bone marrow metastases, two or more prior chemotherapy regimens, history of treatment toxic effects, and prior treatment with carboplatin, mitomycin, or nitrosoureas. Conclusions: Informal assessment of the risk of toxic effects in a patient was found to be common practice among oncologists who enroll patients on phase I trials, and there was strong agreement on the usefulness of several key patient factors for such assessments. Interestingly, interinstitutional variation in opinions and practices were noted, specifically regarding patient-selection bias. Follow-up studies are required to establish if physician-determined assessments of patient risk are consistent and accurate. [J Natl Cancer Inst 86:1685-1693, 1994]

Background. Patients with advanced or metastatic cancer treated in Phase I clinical trials are considered to have a poor prognosis. Survival from first treatment in a Phase I trial was determined for 349 patients. Univariate and multivariate survival analyses were performed to determine whether potential prognostic factors and distinct risk groups could be identified. Methods. Patients were identified retrospectively from a large data base of patients with advanced or metastatic cancer treated in Phase I clinical trials at the University of Chicago between February 1987 and October 1991. Results. With a median follow-up of 29 months, 10% of patients were alive at the time of analysis. Twenty-nine percent were alive 1 year after the initiation of Phase I chemotherapy, and the median survival from first treatment in a Phase I study was 6.5 months. Multivariate analysis indicated that a better pretreatment performance status, a higher pretreatment serum albumin concentration, a lower pretreatment platelet count, no prior cisplatin chemotherapy, and a genitourinary or gynecologic cancer diagnosis were predictive of better survival. Three risk groups incorporating these five variables were identified, with median survivals of 12.7, 7.4, and 3.5 months for the good, intermediate, and poor risk groups, respectively. Conclusion. Patients treated in Phase I clinical trials have a median survival of 6.5 months, even though some patients have been treated at early (subtoxic and potentially subtherapeutic) dose levels. The results of this study may allow the identification of patients who are likely to survive long enough to contribute information on acute and cumulative drug-related toxicities and, possibly, tumor response. Cancer 1994; 74:1965-73.

Background. Cladribine (2-CdA, 2-chlorodeoxyadenosine), a chlorinated adenosine analog, is active in the treatment of hairy cell leukemia and other hematologic malignancies, but its use in treating solid tumors is still under investigation, as is the optimal schedule for administering this drug. The authors conducted a dose-finding study to define the maximal tolerated dose and toxicities of this agent when given to patients with refractory solid tumors having normal renal, hepatic, and bone marrow function. Methods. Cladribine was given as a 1-hour intermittent infusion, repeated daily for 5 days, with a cycle length of 28 days. The initial dose was 4 mg/[m.sup.2], with escalating doses by cohort. Three dosage levels (4, 6, and 8 mg/[m.sup.2]/day) were explored, and patients were observed to determine toxicity. The end points of the study were the definition of the maximally tolerated dose (MTD), toxicity profile, and establishment of a recommended Phase Il dose (RPTD) for cladribine. Results. Eighteen patients were treated; the majority were patients with non-small cell lung cancer and colorectal cancer. The median Cycle-1 leukocyte nadirs for the 4, 6, and 8 mg/[m.sup.2]/day dosage levels were 3100, 2300, and 950 cells/[mu]l (range 800-3500), respectively, and the mean nadir absolute neutrophil counts were 1500, 936, and 482 cells/[mu]l (range 130-2241), respectively. Minimal thrombocytopenia was seen, and no evidence for cumulative myelosuppression was observed. Two patients were hospitalized for neutropenic fevers, both of whom received the 6 mg/[m.sup.2]/day dose. One patient who received the 4 mg/[m.sup.2]/day dose had a transient episode of blindness that occurred during the infusion on Day 3 of Cycle 3. Thorough evaluation of this problem did not reveal an etiology, and it did not recur with further administration of cladribine. No other significant nonhematologic toxicity has been noted. No responses were observed. Conclusions. At the MTD (8 mg/[m.sup.2]/day), the dose-limiting toxicity of this agent is myelosuppression. The RPTD for further testing of this schedule is 6 mg/[m.sup.2]/daily X 5 days.

Background: Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations. Purpose: We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase 11 testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed. Methods: Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 [mu]g/[m.sup.2] was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered. Results: Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 [mu]/[m.sup.2]. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed. Conclusion: We recommend that the phase 11 dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 [mu]g/[m.sup.2], repeated every 6 weeks. Other potentially less myelosuppressive schedule's could be pursued.

Background: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. Purpose: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. Methods: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 [Mu]g/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. Results: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts

Background. Both recombinant interferon alfa and interleukin-2 (IL-2) have been shown to have some activity as single agents in metastatic renal cell cancer (RCC), although their activity is minimal in more common solid tumors. Recent preclinical studies have suggested that the combination of these two agents is especially promising. Methods. Subcutaneous recombinant interferon alfa-2a and IL-2 were administered at one of five dose levels to 33 patients with refractory solid tumors, including 21 patients with RCC. A constant ratio of 5:1 of interferon alfa-2a to IL-2 was used. Interferon alfa-2a and IL-2 were administered three and five times weekly, respectively, for a total of 4 weeks, followed by a rest of 1-3 weeks between cycles. Results. The dose-limiting toxic effects included hypotension, nephrotoxicity, and fatigue. At the recommended Phase II dose of 7.5 million units (MU)/[m.sup.2] of interferon alfa-2a and 1.5 MU/[m.sup.2] of IL-2, 12 patients were treated. Ten of 12 completed the 4-week cycle without modification. Four patients at that dose level had Grade 3-4 toxic effects. Partial responses were observed in 4 of 16 assessable patients with RCC. Conclusions. Subcutaneous interferon alfa-2a and IL-2 can be self-administered safely on an outpatient basis. At tolerable doses, responses can be achieved in metastatic RCC. Cancer 1993; 71:2371-6.

Background: A widely used phase I design in clinical trials of chemotherapy for cancer and for AIDS (acquired immunodeficiency syndrome) allows for dose escalation in cohorts of three to six patients. Escalation continues until a predefined percentage of patients experience unacceptable toxic effects at a given dose level. A safe and maximum tolerated dose (MTD) for phase II study is then determined. This standard phase I study design has serious inadequacies. MTD is not a model-based estimate of the true dose that would yield the targeted dose-limiting toxicity rate. Moreover, this simplistic study design allows some patients in the phase I study to be treated at doses unlikely to have therapeutic efficacy. Purpose: We constructed a novel quantitative assessment design that repetitively evaluates accumulating dose-toxicity data by repeatedly fitting and updating a pharmacodynamic model after small cohorts of patients are treated. The goal was to more accurately estimate the MTD. Methods: One hundred phase I studies were simulated by both the standard and quantitative assessment phase I designs. We compared determination of MTD, frequency of grade 0 leukopenia (no toxicity), and study size in the studies simulated using the standard design with those in the studies simulated using the quantitative assessment design. Results: The median MTD determined from the 100 studies was nearly identical for the two designs: 100 and 95 mg/[m.sup.2] per day for standard and quantitative assessment designs, respectively. However, the interstudy variation in the MTD was decreased in the quantitative assessment design. Moreover, the study size was significantly reduced (P

Background: Cancer patients undergoing chemotherapy with cisplatin-containing regimens often develop anemia. Although the cause is multifactorial, erythropoietin deficiency appears to play an important role. Recombinant human erythropoietin (epoetin) has been reported to be effective in reversing cisplatin-associated anemia in animal studies but not in clinical trials. Purpose: This phase I-II clinical trial was designed to assess the safety and efficacy of treatment with epoetin for anemia associated with cisplatin chemotherapy. Methods: Twenty-one cancer patients treated with cisplatin and manifesting anemia (hemoglobin level

The US FDA Accelerated Approval of sotorasib required the sponsor to conduct a randomized trial that compared the safety and efficacy of the approved dose with a lower dose. These results, recently disclosed, have important implications for patients, payers, oncologists and the pharmaceutical industry.