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Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.

A multicenter phase II study was initiated to investigate the efficacy, toxicity and tolerability of an oral regimen of 9-cis retinoic acid (9CRA) as a differentiation-inducing agent stimulating both retinoic acid receptor (RAR) and retinoic X receptor (RXR). Thirty patients with myelodysplastic syndromes (MDS) were enrolled into the study. The MDS subtypes were distributed as follows: 14 refractory anaemia (RA), four refractory anaemia with ringed sideroblasts (RARS), and 12 refractory anaemia with excess blasts (RAEB). The age ranged from 40 to 81 years (median 70). None of these had previously received treatment for MDS other than supportive therapy. 9CRA (Alitretinoin capsules, kindly provided by Allergan-Ligand Retinoid Therapeutics) was given daily at 60 mg/m2 p.o. for 1 week, followed by an intra-patient escalation to 100 mg/m2 during the second week, up to a maximum of 140 mg/m2. The planned treatment duration was 48 weeks. Twenty-five were available for assessment. One patient (4%) with RA achieved complete hematological remission. Four (16%), two with RA, two with RAEB, had minor responses resulting in decreased transfusion requirements or increased neutrophils. Thus, the overall response rate was 20% in evaluable patients with MDS and 17% in the study group on an intention-to-treat basis. The most frequent side-effects included headache (77%), dry skin (57%), arthralgias (30%), and rash (23%). In conclusion, although modest responses were noted in this study, the treatment tolerability was suboptimal. It is conceivable that a lower dosage schedule may be efficacious and better tolerated so enabling prolonged exposure which may be required to induce a differentiation effect.

Purpose: To compare the toxicity, pharmacokinetics, and efficacy seen in ovarian cancer patients treated with escalating doses of intraperitoneal (I.P.) interleukin-2 (IL-2) by two different infusion schedules., Patients and Methods: Forty-five patients were sequentially entered onto a phase I/II study in groups of four at fixed dosage tiers of 6 x 10(4), 6 x 10(5), 6 x 10(6), and 3 x 10(7) IU/m2/d in either of two schedules: (A) intermittent weekly infusions of 24 hours' duration; or (B) alternating continuous 7-day infusions followed by 7-day intervals without therapy. Eligibility criteria included > or = six courses of prior platinum-based chemotherapy and laparotomy-confirmed persistent or recurrent ovarian cancer., Results: Forty-one eligible patients received I.P. IL-2 and were assessable for toxicity, but six patients were not assessable for response, which left 35 patients assessable for response. Significant locoregional dose-limiting toxicity was seen with the 7-day infusions (including bowel perforation), with 600,000 IU/m2 as the maximum-tolerated dose (MTD), but catheter infection was the only significant complication seen with the 24-hour infusions, for which an MTD was not established. Among 35 assessable patients, there were six laparotomy-confirmed complete responses (CRs) and three partial responses, for an overall response rate of 25.7% (nine of 35). The median survival time of the cohort was 13.7 months and the overall 5-year survival probability was 13.9%. For the nine patients who demonstrated responses (six on the 24-hour infusion and three on the 7-day infusion), the median survival time has not been reached (range, 27 to 90+ months)., Conclusion: I.P. IL-2 is better tolerated as a weekly infusion as compared with a 7-day infusion and demonstrates evidence of possible long-term efficacy in a modest number of patients. A randomized trial is indicated to determine if the prolonged survival seen in this study is a due to I.P. IL-2 therapy or other factors that cannot be controlled for in a single-arm study.

Stout and colleagues [Proc Am Assoc Cancer Res 1993, 34, p. 298] previously reported that both hydrocortisone and tamoxifen increased the free fraction of suramin in human plasma. We examined several corticosteroids as well as tamoxifen for their effects on suramin protein binding and also evaluated hydrocortisone for its ability to modulate suramin activity in PC-3 and MCF-7 cells. Greater than 99% of the suramin was protein bound in undiluted human plasma. However, the free fraction of suramin was increased with the reduced plasma protein levels and increased suramin concentrations. At concentrations ranging from 1 to 30 microM, neither tamoxifen, hydrocortisone, prednisone nor dexamethasone had any effect on the binding of suramin to human plasma, regardless of protein concentrations. Similar results were observed with fetal calf serum. Hydrocortisone also had no effect on suramin activity against PC-3 and MCF-7 cell in vitro. We conclude from these studies that neither corticosteroids nor tamoxifen affect suramin protein binding or its cytotoxic activity.

CI-973 is a water-soluble platinum diamine complex whose antitumor activity is greater than that of cisplatin in some murine tumors. It has shown activity against cisplatin-resistant tumors. This phase II trial had the objectives of determining the therapeutic efficacy of CI-973 in patients with metastatic breast cancer who had been treated with one prior chemotherapy regimen, and of further defining the toxicity of the agent and the reversibility of its toxicity. CI-973 was administered as an intravenous infusion over 30 min with no prehydration or antiemetic programs. Treatment cycles were repeated at 21-day intervals. Patients with histologically confirmed metastatic breast cancer, measurable disease, and good performance status who had received only one prior chemotherapy regimen for metastatic disease were eligible for treatment. Adequate hematologic, renal, and hepatic function were required. A total of 26 patients received a median of two courses of CI-973 (range, 1-18 courses). Hematologic toxicity was severe: nearly all patients experienced granulocytopenia with granulocyte counts of 0 at all dose levels. Nevertheless, neutropenic fever and documented systemic infection were uncommon, and there were no hospitalizations for neutropenic fever or infection. Visceral disease dominated in this patient group. Of the 26 patients, 14 had visceral disease, 6 had bone or bone marrow disease, and 6 had skin, soft-tissue, or lymph-node disease. Of the 26 patients treated, 25 were evaluable for response. There were two partial remissions, one in liver and one in bone, and three minor responses, for a response rate of 8%. Nonhematologic toxic effects were mild and consisted of nausea and vomiting, fatigue, minimum peripheral paresthesia, and hypomagnesemia. Further study of CI-973 at the dose and schedule used in this study is not warranted. Because this agent had no significant extramedullary toxicity, intensification of the dose of CI-973 with concomitant administration of colony-stimulating factors has the potential to improve response in this patient population.

The development of clinically useful drugs is a priority of clinical cancer research. CI-973, [SP-4-3(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-1,4- butanediamine-N,N1) platinum, has been shown in preclinical murine and human tumor models to have activity equivalent or superior to that of cisplatin and carboplatin and to exert activity against cisplatin-resistant cell lines. In addition, preclinical testing suggests a reduced toxicity profile for CI-973 as compared with currently available drugs, especially decreased nephrotoxicity, ototoxicity, and gastrointestinal toxicity. A total of 29 (28 evaluable) patients with solid tumors were treated with intravenous CI-973 given over 30 min every 4 weeks. No routine pre- or post-treatment hydration or antiemetic program was used. The CI-973 doses given were 75, 150, 170, 188, 230, and 290 mg/m2. The dose-limiting toxicity was granulocytopenia. Nausea and vomiting occurred in the majority of patients but was mild to moderate in severity. No renal or auditory toxicity was seen. The maximum tolerated dose (MTD) for patients who had a good performance status, had not received prior radiation therapy to bone marrow, and had not previously been exposed to platinum or stem-cell toxin was 290 mg/m2. For those who had received prior radiation therapy, had a performance status of 2 or worse, or had previously been exposed to platinum or stem-cell toxin, the MTD was 230 mg/m2. The recommended phase II starting doses for these groups of patients are 230 and 190 mg/m2, respectively. No clinical tumor response was seen in this phase I study.

CI-973, a platinum(II) derivative with a 2-methyl-1,4-butanediamine carrier ligand, has activity in cisplatin-resistant tumor models in vitro and in vivo. In a Phase I pharmacokinetic study, 31 patients were treated with CI-973 (24 to 50 mg/m2/day for 5 days; 28-day cycles) given i.v. over 30 min without routine antiemetic prophylaxis or hydration. Of the 29 patients evaluable for maximum tolerated dose determination, most had a performance status of 0 or 1, and most had received prior chemotherapy. Neutropenia was dose limiting at 40 and 50 mg/m2/day. Recovery from neutropenia was generally rapid with nadir counts and recovery usually occurring by Days 15 and 22, respectively. Drug-associated thrombocytopenia was uncommon and never severe, even in patients with Grade 4 neutropenia. Anemia was common, but did not appear dose related. Drug-related nausea and vomiting and changes in renal function were relatively infrequent and mild. No clinically evident ototoxicity was reported, although changes in audiograms were noted in several patients. CI-973 concentrations were measured in plasma ultrafiltrate and urine by high-pressure liquid chromatography. The harmonic mean terminal half-life was 2.0 h. The mean CI-973 renal and nonrenal clearance values were 42.3 and 37.4 ml/min/m2, respectively. The mean recovery of CI-973 in urine was 53% of the administered dose. The mean ratio of CI-973 renal clearance to creatinine clearance was 0.92. Total clearance correlated with creatinine clearance (r2 = 0.63). A relationship between toxicity, expressed as the percentage of reduction in absolute granulocyte count, and area under the CI-973 plasma concentration-time curve was found in a subgroup of "good-risk" patients. This relationship, described well by a sigmoidal Emax pharmacodynamic model, did not hold for patients with extensive prior therapy or poor performance status. A model for toxicity prediction based on dose and creatinine clearance has been derived and will be validated in future studies. The recommended Phase II dose of CI-973 is 30 mg/m2/day for 5 days.

The advantages of hyperthermia for chemotherapy are discussed in detail. These advantages are (a) synergy with chemotherapeutic drugs and also with ionizing radiation, (b) low host toxicity, (c) ease of control (heating precisions in the range of +/- 0.1 degrees C and specific definable localized areas), and (d) low resistance (chemotherapeutic resistance and hyperthermic resistance). The potential for hyperthermia and chemotherapy in the treatment of specific human cancers, both disseminated and solid tumors, are discussed with respect to current therapy and the possible benefit of hyperthermia treatment.

Treatment of mitomycin C with pyrimidine nucleotides in acidic media produced derivatives of 2,7-diaminomitosene in which C-1 was covalently bound to the phosphate group of the nucleotides. On reduction, these derivatives liberated the nucleotides and a mitomycin intermediate that alkylated DNA. Their reduction in the presence of 2'-deoxyguanosine produced some bifunctional alkylation as did mitomycin C. They were readily taken up by L1210 leukemia cells, in which they showed potent cytotoxicity. These properties suggest that they are acting as prodrugs capable of conversion into two active species. The uridylate derivative showed activity comparable to that of mitomycin C against P-388 leukemia in mice.