Split-dose Schedules Research Articles

Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

Efficacy and tolerability of high and low-volume bowel preparation compared: A real-life single-blinded large-population study.

BACKGROUNDLow-volume preparations for colonoscopy have shown similar efficacy compared to high-volume ones in randomized controlled trials (RCT). However, most RCTs do not provide data about clinical outcomes including lesions detection rate. Moreover, real-life comparisons are lacking. AIMTo compare efficacy (both in terms of adequate bowel preparation and detection of colorectal lesions) and tolerability of a high-volume (HV: 4 L polyethylene glycol, PEG) and a low-volume (LV: 2 L PEG plus bisacodyl) bowel preparation in a real-life setting.METHODSConsecutive outpatients referred for colonoscopy were prospectively enrolled between 1 December 2014 and 31 December 2016. Patients could choose either LV or HV preparation, with a day-before schedule for morning colonoscopies and a split-dose for afternoon procedures. Adequate bowel preparation according to Boston Bowel Preparation Scale (BBPS), clinical outcomes including polyp detection rate (PDR), adenoma detection rate (ADR), advanced adenoma detection rate (AADR), sessile/serrated lesion detection rate (SDR) and cancer detection rate and self-reported tolerability of HV and LV were blindly assessed.RESULTSTotal 2040 patients were enrolled and 1815 (mean age 60.6 years, 50.2% men) finally included. LV was chosen by 52% of patients (50.8% of men, 54.9% of women). Split-dose schedule was more common with HV (44.7% vs 38.2%, P = 0.005). High-definition scopes were used in 33.4% of patients, without difference in the two groups (P = 0.605). HV and LV preparations showed similar adequate bowel preparation rates (89.2% vs 86.6%, P = 0.098), also considering the two different schedules (HV split-dose 93.8% vs LV split-dose 93.6%, P = 1; HV day-before 85.5% vs LV day-before 82.3%, P = 0.182). Mean global BBPS score was higher for HV preparations (7.1 ± 1.7 vs 6.8 ± 1.6, P < 0.001). After adjustment for sex, age and indications for colonoscopy, HV preparation resulted higher in PDR [Odds ratio (OR) 1.32, 95%CI: 1.07-1.63, P = 0.011] and ADR (OR 1.29, 95%CI 1.02–1.63, P = 0.038) and comparable to LV in AADR (OR 1.51, 95%CI 0.97-2.35, P = 0.069), SDR and cancer detection rate. The use of standard-definition colonoscopes was associated to lower PDR (adjusted OR 1.59, 95%CI: 1.22-2.08, P < 0.001), ADR (adjusted OR 1.71, 95%CI: 1.26–2.30, P < 0.001) and AADR (adjusted OR 1.97, 95%CI: 1.09-3.56, P = 0.025) in patients receiving LV preparation. Mean Visual Analogue Scale tolerability scored equally (7, P = 0.627) but a ≥ 75% dose intake was more frequent with LV (94.6% vs 92.1%, P = 0.003). CONCLUSIONIn a real-life setting, PEG-based low-volume preparation with bisacodyl showed similar efficacy and tolerability compared to standard HV preparation. However, with higher PDR and ADR, HV should still be considered as the reference standard for clinical trials and the preferred option in screening colonoscopy, especially when colonoscopy is performed with standard resolution imaging.

Safety of Split First Dosing Vs Standard Dosing Administration of Daratumumab Among Multiple Myeloma Patients Treated in a US Community Oncology Setting: A Real-World Observational Study

INTRODUCTIONDaratumumab (DARA) is a human IgGκ monoclonal anti-CD38 antibody for treatment of multiple myeloma (MM). In clinical trials, median durations for the 1st, 2nd and subsequent infusions were 7.0, 4.3 and 3.5 hours, respectively. To optimize the first infusion duration of DARA, the US Oncology Network (USON), a community oncology practice network, implemented a split first dose protocol. The USON split first dose protocol requires 2 IV bags, one for Day 1 and one for Day 2 of consecutive days. On each day, DARA is diluted with normal saline to a total volume of 500 mL. On each day, DARA is administered at 50 mL/hour for one hour. If no infusion events occur, the infusion rate can be increased in 50 mL/hour increments every hour to a maximum of 200 mL/hour. While the split first dose may increase convenience, limited information is available on the safety of split first dose DARA. METHODSThis was a retrospective, observational study of adult MM patients who initiated DARA in routine care within USON between 11/01/2015 - 06/30/2017 to compare infusion times and safety of DARA split first dose vs DARA standard dose schedule (i.e., 1 infusion of 16 mg/kg per FDA-approved prescribing information). In this study, patients were grouped into either the split first dose cohort or the standard dose schedule cohort according to the dosing schedule that they had experienced. Data were sourced from USON's electronic healthcare record system. Information on infusion reactions was available only through chart review, which was conducted among a random sample of patients in each study cohort. Descriptive analyses were conducted to compare demographic, clinical and treatment characteristics of MM patients who received split first dose schedule vs standard dosing schedule. Chi-square tests or Fisher's exact tests were used to assess associations between categorical variables. ANOVA/t-tests or Kruskal-Wallis tests were used to assess associations for continuous variables. A p-value of <0.05 was considered as statistically significant. RESULTSOf the 622 patients included in the landscape analysis, 365 (58.5%) had received the split first dose schedule and 258 (41.5%) had received the standard dosing schedule. Overall, the median age was 63.6 years, 54.2% male and 78.3% Caucasian. The utilization of the split first dose schedule increased significantly over time with more patients in 2017 Q2 having received split dose vs standard dose (p< 0.0001). Karnofsky performance status (KPS) scores differed significantly between patients treated with split first dose vs standard dose (p=0.02). No other baseline differences between groups were found. The median infusion duration was 4.5 hours for Day 1 of split first dose and 6.5 hours for standard dose (p<0.0001). Among patients selected for chart review (n = 302), 47.8% (88/184) of split first dose patients and 48.3% (57/118) of standard dose patients experienced at least one infusion reaction. The most common infusion reactions included lower-respiratory (26.1%), upper-respiratory (17.2%) and gastrointestinal reactions (12.5%), chills (8.9%), flushing (6.6%), with no statistically significant differences between study groups for any infusion reaction. Among patients treated with split first dose DARA, 3.8% experienced an infusion reaction during Day 2 of the split dose schedule. CONCLUSIONSAs a retrospective observational study at community-based oncology clinics, these findings provide real-world evidence on the infusion time and safety of the first infusion of DARA. This study found that the utilization of split first dose has increased over time. Interestingly, more patients in the split dose group had higher KPS scores than patients in the standard dose group, which may be due to selection of patients, at least initially, for the split first dose. This study found also that the length of the first day of the split first dose schedule is shorter than the length of the standard dosing schedule. Additionally, although determination of severity or grade was not feasible in this study, the proportion of patients in split first and standard dosing schedule groups who experienced infusion reactions was equal. This study suggests that the split first dose is comparable to the standard dose schedule and may be a practical option for patients and institutions seeking options to manage the operational considerations of DARA administrations. DisclosuresRifkin:Takeda: Consultancy; EMD Serono: Consultancy; Sandoz: Consultancy; Celgene: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Amgen: Consultancy. Singer:Janssen Scientific Affairs, LLC: Research Funding. Aguilar:McKesson Specialty Health: Employment. Baidoo:McKesson Specialty Health: Employment. Maiese:Janssen Scientific Affairs,LLC: Employment, Equity Ownership.

A Phase 1b Dose-Escalation Study of Split-Dose Oprozomib (ONX0912) in Patients with Hematologic Malignancies

AbstractAbstract 203 Background:Oprozomib (OPZ, formerly ONX 0912), a structural analog of carfilzomib (CFZ), is an orally bioavailable, next-generation proteasome inhibitor being evaluated in hematologic malignancies and solid tumors. Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor. In an earlier dose-escalation study of once-daily (QD) OPZ in patients with advanced refractory solid tumors, the maximum tolerated dose (MTD) was 150 mg QD, leading to exploration of a split-dose schedule with the drug administered twice daily (BID). The present phase 1 study (NCT01416428) is evaluating OPZ administered using the split-dose schedule in patients with hematologic malignancies. Methods:This is an ongoing, phase 1b, open-label, dose-escalation study of OPZ in patients with hematologic malignancies. The primary objectives are to evaluate safety and tolerability and to determine the MTD. Secondary objectives of the study include pharmacokinetic and pharmacodynamic analyses. OPZ is administered PO on days 1–5 of a 14-day cycle using a standard 3 + 3 dose-escalation scheme. Treatment was initiated at 120 mg (60 mg BID), with an interval of 4–6 h between doses, with escalation in 30-mg increments in successive cohorts until MTD is determined. Tumor response is assessed by investigator. Results:As of June 15, 2012, 9 patients have been enrolled in the study, 3 in each of the 120-mg, 150-mg, and 180-mg dosing cohorts. No dose-limiting toxicities have been observed. Enrollment is ongoing at 210 mg/day. The median age of all patients is 67 years (range 53−81) and prior therapies included a median of 4 chemotherapy regimens (range 2−8). Patients have received a median of 5 cycles of treatment with OPZ, including 4 patients who have received ≥6 cycles. Dose reduction was required by only 1 patient in the 180-mg (90 mg BID) group for Grade 3 diarrhea and abdominal pain. Gastrointestinal (GI) AEs predominantly of Grade 1/2 in severity were the most common, with diarrhea and nausea each occurring in 7 patients, and vomiting occurring in 6 patients. The majority of GI AEs improved or resolved with concomitant medications. Thrombocytopenia was the only Grade 3/4 AE reported in more than 1 patient, occurring in 3 patients (1 at each dose level). Notably, no events of peripheral neuropathy were noted in patients in the first 3 dosing cohorts. AEs led to discontinuation in 2 patients at the 180-mg dose level, and no deaths have been reported. OPZ showed dose-dependent exposure across the 120- to 180-mg dose levels. Patients receiving split dosing had similar total exposure and lower Cmax than patients receiving QD dosing of the same total daily dose, although there was high inter-patient variability. Dose-dependent proteasome inhibition was observed in whole blood and increased from the first to the second of the split daily doses. Proteasome inhibition levels were similar to those achieved with single-dose equivalents and were >80% at the 180-mg dose level. Eight of 9 patients are evaluable for efficacy. There was preliminary evidence of anti-tumor activity of ≥SD across all doses, including 1 patient with chronic lymphocytic leukemia who attained a PR after prior exposure to 3 lines of therapy, and 1 PR and 1 MR in patients with multiple myeloma. Conclusions:Oral OPZ was generally well tolerated using a split-dose schedule in this phase 1 trial in patients with hematologic malignancies. AEs were generally mild and manageable. An MTD has not been reached at cumulative doses up to 180 mg/d (90 mg BID). Dose-dependent proteasome inhibition was observed, with >80% inhibition at the highest dose tested. OPZ also demonstrated encouraging clinical activity across the first 3 dose levels in heavily pretreated patients. Dose escalation will continue until the MTD is reached, with planned phase 2 expansion at the MTD in patients with hematologic malignancies. Disclosures:Off Label Use: Oprozomib is in Phase 1 clinical trials for hematologic malignancies and is not approved by the FDA for any use. Lee:Onyx Pharmaceuticals: Employment. Wong:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Gillenwater:Onyx Pharmaceuticals: Employment. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau.

Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.

Phase I trial of pulse-dose vorinostat with flavopiridol in solid tumors.

e13511 Background: Preclinical data show that the histone deacetylase inhibitor vorinostat (V) enhances chemotherapy at levels of > 2.5 μM. However the approved oral dose of V of 400 mg/d inconsistently achieves this level in pts. We sought to develop an intermittent oral pulse-dose schedule of V to increase serum drug levels. We combined V with the pan-cyclin dependent kinase inhibitor flavopiridol (F) based on data that sequential treatment with F increases V-induced apoptosis. Methods: This is a phase I trial of V + F in pts with advanced solid tumors. One week before combination therapy, V alone was given daily PO for 3 d (cycle -1). Combination treatment began with cycle 1. V was initially given on d 1-3 and 8-10 of each 21-d cycle. F was given IV on d 2 and d 9 of each cycle. Due to neutropenia, this was modified to V on d 1-3 and 15-17, and F on d 2 and 16, of each 28-d cycle. A split-dose schedule of F 30 mg/m2 over 30 min followed by 30 mg/m2 over 4 h was also investigated. Results: 34 pts were treated; 31 were evaluable for response. Pt characteristics: median age 59 (range 38-85), ECOG PS 1 (0- 1), prior regimens 4 (1-11). With V given on d 1-3 and 8-10, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m2 over 1 h. Dose-limiting toxicities (DLT) were neutropenia, leukopenia, thrombocytopenia, hemorrhage, and pulmonary embolus. With V given on d 1-3 and 15-17, the MTD was V 800 mg/d and F 30 mg/m2over 30 min and 30 mg/m2 over 4 h. DLTs were neutropenia and infection. V pharmacokinetics increased with dose and the increase was greater than proportional. Mean V Cmax of pts treated at the 800 mg dose was 4.8 μM (± 2.8). V Cmax ≥ 2.5 μM was achieved in 86% of pts treated at the MTD. F co-administration increased the Cmax of V by 27% (95% CI 11%-43%). Flavopiridol Cmax of ≥ 2 μM was achieved in 90% of patients. The best response was stable disease in 8 pts for an average of 5.5 m (range 1.6-13.2 m). Conclusions: Intermittent administration of high dose oral V in combination with F is feasible and achieves target serum levels > 2.5 μM associated with in vitro synergy. V concentrations higher than previously reported with oral dosing were achieved without undue toxicity. The recommended phase II dose is V 800 mg once daily for 3 d (d 1- 3) with F on d 2 given as 30 mg/m2 over 30 min followed by 30 mg/m2 over 4 h, every 14 d. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck

Mode of Growth Hormone Action in Osteoblasts

Growth hormone (GH) affects bone size and mass in part through stimulating insulin-like growth factor type 1 (IGF-1) production in liver and bone. Whether GH acts independent of IGF-1 in bone remains unclear. To define the mode of GH action in bone, we have used a Cre/loxP system in which the type 1 IGF-1 receptor (Igf1r) has been disrupted specifically in osteoblasts in vitro and in vivo. Calvarial osteoblasts from mice homozygous for the floxed IGF-1R allele (IGF-1R(flox/flox)) were infected with adenoviral vectors expressing Cre. Disruption of IGF-1R mRNA (>90%) was accompanied by near elimination of IGF-1R protein but retention of GHR protein. GH-induced STAT5 activation was consistently greater in osteoblasts with an intact IGF-1R. Osteoblasts lacking IGF-1R retained GH-induced ERK and Akt phosphorylation and GH-stimulated IGF-1 and IGFBP-3 mRNA expression. GH-induced osteoblast proliferation was abolished by Cre-mediated disruption of the IGF-1R or co-incubation of cells with an IGF-1-neutralizing antibody. By contrast, GH inhibited apoptosis in osteoblasts lacking the IGF-1R. To examine the effects of GH on osteoblasts in vivo, mice wild type for the IGF-1R treated with GH subcutaneously for 7 days showed a doubling in the number of osteoblasts lining trabecular bone, whereas osteoblast numbers in similarly treated mice lacking the IGF-1R in osteoblasts were not significantly affected. These results indicate that although direct IGF-1R-independent actions of GH on osteoblast apoptosis can be demonstrated in vitro, IGF-1R is required for anabolic effects of GH in osteoblasts in vivo.

Dose response of rat retinal microvessels to proton dose schedules used clinically: a pilot study

Purpose: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation Methods and Materials: The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls. Results: Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values ( p < 0.001) following 28 Gy and following 20 Gy ( p < 0.05) in a single dose. Endothelial cell loss was the same for single- and split-dose schedules. Progressive endothelial cell loss produced vessel collapse and acellular vessel strands. Endothelial cells were in the G 0 phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss. Conclusion: The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density.

In vitro and in vivo anti‐tumor activity of L‐glutamic acid γ‐monohydroxamate against L1210 leukemia and B16 melanoma

A glutamine analogue, L-glutamic acid gamma-monohydroxamate (GAH) demonstrated complete cytotoxicity against L1210 cells in culture and marked anti-tumoral activity in vivo against L1210 leukemia and B16 melanoma. In vitro, GAH caused concentration-dependent inhibition of L1210 cell growth, with complete cell death being reached at 72 hr and at a 500 microM concentration. A minimal incubation time of 38 hr with 500 microM GAH was necessary to obtain complete cell death at 72 hr. During incubation, GAH is metabolized to hydroxylamine. Hydroxylamine acts as the active form of GAH, since the concentration-dependent inhibition of cell growth caused by hydroxylamine is the same as that observed with GAH. The cytotoxic effects of GAH and hydroxylamine on L1210 cells were not reversed or prevented by L-glutamine or L-glutamic acid and purine nucleosides but were prevented or reversed by pyruvate, 2-oxaloacetate and 2-oxoglutarate. In vivo, GAH considerably increased survival of mice bearing L1210 leukemia or a solid tumor, the B16 melanoma. Antitumor activity of GAH against L1210 leukemia and B16 melanoma was schedule-dependent. The administration of GAH 3 times daily was more effective than a twice daily treatment and the maximum ILS was observed using split-dose schedules on days 1 through 3 and 7 through 9 without noticeable toxicity. Under these conditions hydroxylamine is highly toxic, suggesting that in vivo GAH might act as an hydroxylamine releaser in the tumor cells and is not significantly metabolized in the body.

High-dose therapy with ftorafur in gastrointestinal cancer.

Our group started experimental and clinical investigations with ftorafur because this drug shows a remarkable low rate of toxicity compared with 5-fluorouracil (5-FU) [31, 32]. Furthermore, the reported long serum half-life of ftorafur of approximately 10–16 h for the beta-phase [1, 4, 10, 19, 20] makes the drug interesting for split-dose schedules. In comparison with single daily injections, split-dose administration of a drug with a long serum half-life may offer the advantage of maintaining a higher level of cytocidal activity over a longer period of time without the problem of serious side effects, especially in the nervous system, as can be observed after a single high-dose injection of ftorafur [27].KeywordsGastrointestinal TumorBarbituric AcidCytostatic DrugEhrlich Ascites Tumor CellMale NMRI MouseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Results of a E.O.R.T.C. randomized trial of cyclophosphamide and radiotherapy in inoperable lung cancer: Prognostic factors and treatment results

A randomized cooperative clinical trial has been conducted in inoperable carcinoma of the lung. One hundred and eighty-seven patients under age 72 of both sexes of all cell types were admitted provided they had had no previous surgery, chemotherapy or radiotherapy with the exception that patients having received less than 2g of cyclophosphamide or less than 2 weeks of chemotherapy of any kind could be included. Treatment was assigned by randomization, stratified by institution and cell type, to one of the following treatments: (1) continuous radiotherapy ( 6000 rad at the rate of 1000 rad per week), (2) split-course radiotherapy ( 3 series of 2000 rad each administered in three 2-week periods separated by 8-week intervals), (3) continuous radiotherapy plus cyclophosphamide, (4) split-course radiotherapy plus cyclophosphamide. Cyclophosphamide was given at the dose of 20 mg/kg i.v. or i.m. every 15 days starting 15 days after the completion of continuous radiotherapy or 15 days after the first course of radiotherapy for those receiving the split-dose schedule. No statistically significant differences in survival were seen between treatment groups.

Methyl-CCNU in malignant melanoma--a divided dose schedule of administration.

Methyl-CCNU (NSC-95441) was administered to patients with malignant melanoma in a split dose schedule. Nausea and vomiting were eliminated as clinical problems during therapy. Response rate to the drug seemed somewhat lower than the average of three previously reported disease-oriented phase II trials, though the difference was not significant statistically. The time course of myelosuppression seemed comparable to that seen with a single dose schedule of administration.