A phase II study of Didemnin B (NSC 325319) in advanced malignant melanoma: an Eastern Cooperative Oncology Group study (PB687)

Purpose: Didemnin B is a novel marine natural product cyclic depsipeptide containing unusual amino acid moieties. This agent demonstrates promising preclinical antitumor activity, including activity against B16 melanoma and against melanoma isolates in the human tumor stem cell assay.Methods: We conducted a phase II study of Didemnin B, given in Cremophor, at a starting dose of 4.2 mg/m2/IV q 28 days. Patients with measurable metastatic or advanced malignant melanoma were eligible. All patients were previously untreated with chemotherapy and had performance status 0 or 1. Doses were escalated to 4.9 and 5.6 mg/m2 in cycles 2 and 3, respectively.Results: Nineteen patients were entered and treated with a median of one cycle per patient. Eight of these patients went off study for toxicity including 7 with anaphylactoid reactions in the first or second cycle. One patient went off study after 3 cycles with severe myopathy, a newly described toxicity. Two were not evaluable for response and five were considered stable, including one patient with a transient PR of soft tissue disease in the first cycle. Another patient had stable disease for twelve cycles before progressing and one went off study electively after 3 cycles, for a total of 7 patients with stable disease. One patient with a measurable partial remission (PR) and went off study after three cycles due to severe myopathy, a then newly-described toxicity. No hematologic toxicity was seen. Nausea and vomiting were controlled with anti-emetics.Conclusions: This study was indeterminate with respect to the activity of Didemnin B in melanoma. Signs of activity were seen, particularly in soft tissue masses, though a large number of patients could not be evaluated fully for activity due to the occurrence of anaphylactoid reactions. This study does not preclude a clinically important level of activity for Didemnin B.     

Phase II study of epirubicin in advanced malignant melanoma

Summary Twenty patients with advanced malignant melanoma refractory to conventional chemotherapy, were entered into a Phase II study of epirubicin, one of the new doxorubicin analogues. The drug was given at a dose of 90 mg/m² IV every 3 weeks. One partial response and three disease stabilizations were observed. Nausea and vomiting and alopecia were common. Mild to moderate leukopenia occurred in 6 patients. Three cases of reversible ST-T changes were recorded. The observed response rate of 5% with a 39.2% probability of a true response rate 10%, does not suggest that epirubicin, in the dose and schedule chosen, is active in metastatic malignant melanoma.     

Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study

Malignant melanoma is increasing infrequency at a rapid rate in the UnitedStates. Metastatic disease ischemoresistant with DTIC considered themost active single agent. CI-980 is asynthetic mitotic inhibitor that blocks theassembly of tubulin and microtubules. Ithas shown cytotoxic activity against abroad spectrum of murine and human tumorcell tines. CI-980 can cross the bloodbrain barrier, is effective when givenorally or parenterally, and is activeagainst multidrug resistant cell linesoverexpressing P-glycoprotein. In thistrial, patients with disseminated melanomawith measurable disease, SWOG performancestatus of 0–1, no prior chemotherapy orimmunotherapy for metastatic disease, andadequate hepatic and renal function, wereenrolled. Treatment with CI-980 was givenby 72 h continuous IV infusion at a doseof 4.5 mg/m²/day, days 1–3 every 21 days. Twenty-four patients were registered onthis study with no patients ineligible. They ranged in age from 33–78 withperformance status of 0 in 15 patients and1 in 9 patients. Nineteen patients hadvisceral disease with 12 having liverinvolvement. There were no confirmedresponses. The overall response rate was0% (95% CI 0%–14%). The medianoverall survival is eleven months (95% CI4–14 months). The most common toxicitieswere hematologic and consisted ofleukopenia/granulocytopenia and anemia,with nausea/vomiting andmalaise/fatigue/weakness also frequent. CI-980 administered at this dose andschedule has insufficient activity in thetreatment of disseminated malignantmelanoma to warrant furtherinvestigation.     

A phase II study of Didemnin B (NSC 325319) in advanced malignant melanoma: an Eastern Cooperative Oncology Group study (PB687)

PURPOSE: Didemnin B is a novel marine natural product cyclic depsipeptide containing unusual amino acid moieties. This agent demonstrates promising preclinical antitumor activity, including activity against B16 melanoma and against melanoma isolates in the human tumor stem cell assay. METHODS: We conducted a phase II study of Didemnin B, given in Cremophor, at a starting dose of 4.2 mg/m2/IV q 28 days. Patients with measurable metastatic or advanced malignant melanoma were eligible. All patients were previously untreated with chemotherapy and had performance status 0 or 1. Doses were escalated to 4.9 and 5.6 mg/m2 in cycles 2 and 3, respectively. RESULTS: Nineteen patients were entered and treated with a median of one cycle per patient. Eight of these patients went off study for toxicity including 7 with anaphylactoid reactions in the first or second cycle. One patient went off study after 3 cycles with severe myopathy, a newly described toxicity. Two were not evaluable for response and five were considered stable, including one patient with a transient PR of soft tissue disease in the first cycle. Another patient had stable disease for twelve cycles before progressing and one went off study electively after 3 cycles, for a total of 7 patients with stable disease. One patient with a measurable partial remission (PR) and went off study after three cycles due to severe myopathy, a then newly-described toxicity. No hematologic toxicity was seen. Nausea and vomiting were controlled with anti-emetics. CONCLUSIONS: This study was indeterminate with respect to the activity of Didemnin B in melanoma. Signs of activity were seen, particularly in soft tissue masses, though a large number of patients could not be evaluated fully for activity due to the occurrence of anaphylactoid reactions. This study does not preclude a clinically important level of activity for Didemnin B.     

Phase II trial of carboplatin in patients with advanced melanoma

Summary We report the results of a phase II evaluation of carboplatin (CBDCA) in 45 patients with advanced malignant melanoma. Of the 43 evaluable patients, 6 had been treated previously with chemotherapy; 11 had been treated with immunotherapy. The initial dose was 400 mg/m² i.v. every 4 weeks; the dose was modified as required to achieve moderate myelosuppression. There was one complete response (duration 16 months) and six partial responses, for a major objective response rate of 16%. Toxicity consisted primarily of acute nausea and vomiting, and thrombocytopenia. The activity of CBDCA in this disease is similar to that of cisplatin and dacarbazine.     

A phase II trial of pyrazine diazohydroxide in patients with disseminated malignant melanoma and no prior chemotherapy--Southwest Oncology Group study

Malignant melanoma is rapidly increasing inthe United States. Metastatic diseaseresponds poorly to currently availablechemotherapy. Pyrazine diazohydroxide(PZDH) is a new agent inhibiting DNAsynthesis that is active in mouse tumormodels and human xenografts and lackscross resistance withmultiple standard agents. In this phase IItrial, patients with no prior chemotherapyor immunotherapyfor metastatic disease and performancestatus (SWOG) of 0–1, were treated withpyrazine diazohydroxide at a dose of 100 mg/m²/day by IV bolus injectionover 5–15 minutes for 5 consecutive daysevery 6 weeks. There were 23 eligiblepatients entered on this trial with 74%having PS of 0 and 91% having visceralmetastases. There were no confirmed anti-tumor responses. Theoverall response rate is 0% (95% CI 0%–15%). Median overall survival is sixmonths (95% CI 5-8months). The most common toxicities were hematologic and consisted of lymphopenia,thrombocytopenia, anemia, and leukopenia. Fatigue, and nausea and vomiting were thenext mostcommon toxicities. Pyrazine diazohydroxideby this dose and schedule has insufficientactivity in thetreatment of disseminated malignantmelanoma to warrant further investigation.     

N-Methylformamide in advanced squamous cancer of the uterine cervix: an Eastern Cooperative Oncology Group phase II trial

Purpose: Preclinical and clinical data support the studyof polar-planar compounds such as N-Methylformamide (NMF) inadvanced squamous cell carcinoma of the uterine cervix (SCC).This phase II trial sought to determine the efficacy andtoxicities of NMF in patients with advanced SCC. Patientsand methods: Eligibility for this trial requiredbidimensionally measurable squamous or adenosquamous cellcancer of the uterine cervix incurable by surgery or radiationtherapy, ECOG performance status of 2, no prior NMF and nomore than one prior chemotherapy regimen. Patients receivedNMF at 2000 mg/m² intravenously over 15–30 minutes days 1,8 and 15. The cycle was repeated every 42 days. A single doseescalation of 25%, 500 mg/m² was made after the firstcycle if the toxicities did not exceed grade I for hepatictoxicity and grade II for nausea and vomiting. Results:From July 1987 through September 1998, 21 patients withadvanced squamous cell carcinoma of the uterine cervix wereentered on study. Two patients were ineligible because therewas no pretreatment SGOT on one and the other deterioratedprior to drug approval. Therefore, 19 patients were include inthe analysis of response and survival. Four were inevaluable,3 due to inappropriate tumor evaluation and I secondary tograde III vomiting, who went off study. These patients wereincluded in the denominator while computing the results. Therewere 2 deaths, one due to pulmonary hemorrhage fromperforation during central venous insertion and one due todisease. 30% (6/19) patients had toxicities, EasternCooperative Oncology Group (ECOG) grade III or higher and 2 ofthese patients suffered multiple grade III toxicities. Therewere no complete or partial responses. Conclusion: Inthis population, NMF in the dose and schedule employedexhibited no clinical activity.     

Phase II trial of fotemustine in patients with metastatic malignant melanoma

Summary Fotemustine is a novel chloroethylnitrosourea, that readily penetrates the blood brain barrier. Preliminary French studies reported encouraging results with fotemustine in patients with cerebral metastases of malignant melanoma. Thirty-one patients with histologically confirmed metastatic malignant melanoma were entered on a phase II trial. The treatment regimen consisted of fotemustine, administered intravenously as a rapid infusion, at a dose of 100 mg/m² on day 1, 8 and 15 every 4 to 5 weeks. Objective response (CR+PR) was documented in 3 patients. Median time to treatment failure (TTF) was 44 days and median survival was 164 days. Life threatening toxicity did not occur; hematological toxicity and nausea and vomiting were the most common toxicities. Despite a somewhat disappointing response rate, objective responses were documented in patients with cerebral metastases. Since no other chemotherapeutic agent has shown therapeutic efficacy in cerebral metastases from malignant melanoma fotemustine therefore warrants further study.     

Phase II trial of topotecan in advanced gastric cancer: A Southwest Oncology Group study

Topotecan (NSC 609099) is a camptothecin analogue that demonstrated activity against a variety of human tumors in preclinical studies. A phase II trial was performed with topotecan given to patients with locally advanced or metastatic adenocarcinoma of the stomach. Topotecan was administered IV Bolus over 30 minutes on a daily × 5 schedule, every three weeks, with a starting dose of 1.5 mg/m². Twenty patients were entered onto the study, all of whom were eligible. All patients were evaluable for toxicities. Half of these patients experienced at least one Grade 4 hematologic toxicity, comprised of either granulocytopenia or leukopenia (4 patients with both, 3 patients with grade 4 granulocytopenia, and 2 patients with only grade 4 leukopenia). Other non-life threatening (Grade 3) toxicities included nausea (2 patients), weakness (2 patients), weight loss (1 patient), blurred vision (1 patient), diarrhea (1 patient) and malaise/fatigue/lethargy (1 patient). Two patients achieved a partial response, for an overall response rate of 10% (95% confidence interval of 1.2 to 31.7%). The median survival for the 20 patients was five months.     

Phase II study of trimetrexate in malignant melanoma: A National Cancer Institute of Canada Clinical Trials Group Study

Summary The National Cancer Institute of Canada Clinical Trials Group carried out a phase II trial of trimetrexate given in a daily × 5 intravenous bolus schedule every 3 weeks in patients with measurable metastatic malignant melanoma who had not received previous chemotherapy. Significant hematologic toxicity was observed and was not obviously related to the dose of trimetrexate. No responses were seen in 18 patients. We did not find trimetrexate given as described to be effective in metastatic malignant melanoma.     

A structure--activity study of seven new water soluble nitrosoureas.

The in vitro alkylating activity, carbamoylating activity, decomposition rates and octanol-water partition coefficients (Log P) of seven water soluble chloroethylnitrosourea antitumor agents and a reference lipid soluble analog were correlated with their biological activities in mice. The alkylating activity of each compound demonstrated a significant inverse linear correlation with both the decomposition rate in 0.1 M sodium phosphate buffer. pH7.4 (r = -0.92,P< 0.01), and the molar ld₁₀ dose (r = 0.87, P< 0.01). A direct relationship was found between the Log P values and both the alkylating activity (r = -0.86. P< 0.01) and the molar ld₁₀ dose (r = 0.77, P< 0.025). However, the addition of the variable. Log P, in multiple regression analysis did not contribute significantly to any of the direct correlations of chemical parameters with biological variables. In comparison, carbamoylating activity did not function as an independent variable for the relative myelotoxicity or lethality of each compound. All water soluble drugs except for chlorozotocin and 1-(2 chloroethyl)-3-(β-d-glucopyranosyl)-1-nitrosourea, the two analogs with glucose carriers, produced a significant reduction in circulating neutrophils at their respective ld₁₀ doses. There was no correlation between relative myelotoxicity and alkylating activity, carbamoylating activity or Log P. The glucose moiety appears to function as an independent variable for reducing nitrosourea cytotoxicity to bone marrow cells without significantly altering antitumor activity.     

Phase II study of amonafide in advanced and recurrent sarcoma patients

Summary The activity of amonafide, a benzisoquinoline-1,3-dione, was assessed in 15 patients with advanced or recurrent sarcoma (11 previously treated). Eligible patients had ECOG performance status 0–2, and acceptable renal, hepatic and bone marrow function. Amonafide 300 mg/m² was given intravenously over one hour daily on five consecutive days, every 3 weeks. Leukopenia and granulocytopenia were the most common and severe toxicities (grade 3 or 4 toxicity in 20% and 27% of patients, respectively). Local irritation and nausea/vomiting, the most common nonhematologic toxicities, were generally mild. No objective responses were seen, though 2 patients had brief stabilization of disease. Amonafide at this dose and schedule has no activity against advanced, recurrent sarcoma.     

The effect of alkylating agents and other drugs on the accumulation of melphalan by murine L1210 leukaemia cells in vitro

The effect of cytotoxic and other drugs on the accumulation of melphalan by L1210 murine leukaemia cells was studied. We have confirmed that uptake is an active process competitively inhibited by l-leucine. In 36 experiments in amino acid-free medium the mean concentration of melphalan taken up was 225 pmoles/10⁶ cells. High pressure liquid Chromatographie analysis showed that the majority of the drug is present as free native melphalan. 1, 3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) was the only drug that stimulated accumulation, but without significant effect on influx or efflux rates. Busulphan, chlorambucil, cyclophosphamide, interferon, methotrexate and prednisolone had no effect on accumulation after 30 min melphalan transport. Adriamycin, CCNU, methyl CCNU, mustine and vincristine all impaired melphalan accumulation as did the non-cytotoxic drugs aminophylline, chlorpromazine and ouabain. Adriamycin, aminophylline, chloropromazine, indomethacin and ouabain all reduced melphalan influx.     

Mechanism of action of 2-haloethylnitrosoureas on deoxyribonucleic acid. Nature of the intermediates from nitrosourea decomposition.

Direct current (DC) and differential pulse polarographic analyses were used to measure the rates of decomposition of a series of 2-haloethylnitrosoureas in aqueous solution. Measured by these methods, the rates of the first and rate-determining step which show a marked pH and solvent dependence agree with the overall rate of decomposition measured by gas evolution. In the 1,3-bis(haloethyl)-1-nitrosourea series, changing the nature of the halogen X has a small effect on the rate of decomposition. In the 3-cyclohexyl-1-(2-haloethyl)-1-nitrosourea series, changing X for OH or OCH₃ results in the rate of hydrolysis being reduced considerably. A free—NH₂ group in the nitrosourea structure as in CNU, MNU, ENU, CPNU, 4-CBNU and 5-CPNU accelerates considerably the rate of decomposition relative to the BCNU and CCNU series. Arrhenius parameters for the decomposition in aqueous pH 7.1 solution in the temperature range 28–47° were obtained for BFNU, BCNU and BBNU: log A, ?20.1± 1.4,?21.6± 0.7 and ?22.3±1.6; E_a, 24.4 ± 2.0, 26.5± 1.0 and 27.2 m 2.3 kcal/mole. The corresponding values for BINU were estimated as log A,?23.3± 3.0; E_a, 28.0± 3.0 kcal/mole. Examination of the decomposition products of 1,3-bis(2-chloropropyl)-1-nitrosourea (BCNU-β-Me) and 1,3-bisl 1-(chloromethyl)ethyl]-1-nitrosourea (BCNU-α-Me) favors decomposition pathway B via the diazohydroxide and cyclic chloronium ion for BCNU-β-Me and via the diazohydroxide and/or 2-chloro-1-methylethyl carbonium ion for BCNU-α-Me. While there is no evidence for the contribution of pathway A via a 2-imino-N-nitrosooxazolidinone for these compounds, consideration of product type and yields implicates a third decomposition pathway, via a 1,2,3-oxadiazoline intermediate. Additional evidence for an oxadiazoline intermediate is obtained by the isolation of 2-bromoethanol when BCNU is decomposed in the presence of a high concentration of sodium bromide.     

Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

PURPOSE: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. PATIENTS AND METHODS: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. RESULTS: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. CONCLUSIONS: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.     

Phase II trial to topotecan in hepatocellular carcinoma: A Southwest Oncology Group study

Hepatocellular carcinoma remains a highly chemoresistant neoplasm. In this study of the topoisomerase I inhibitor topotecan a response rate of 13.9% (95% confidence interval 4.7%–29.5%) was obtained utilizing a five consecutive day bolus infusion schedule. There were no complete responses and the median survival was only eight months. Furthermore, treatment with topotecan produced significant toxicity with two-thirds of patients experiencing life-threatening (grade 4) neutropenia. When used in this dose and schedule, topotecan does not appear to be effective for patients with advanced hepatocellular carcinoma.     

A randomized phase II study of two schedules of bryostatin-1 (NSC339555) in patients with advanced malignant melanoma: A National Cancer Institute of Canada Clinical Trials Group study

Purpose: This study addressed theefficacy and toxicity of the novel compoundBryostatin-1 (NSC 339555), a novel agentwith antineoplastic, hematopoietic andimmunomodulatory activity in a variety ofin vitro and in vivo systems. Patients and methods: This phase IIstudy randomly assignedchemotherapy-naïve patients withuntreated metastatic melanoma andmeasurable disease to two schedules oftreatment: Arm A, 25 g/m²bryostatin-1 given as a 24 hour continuousinfusion weekly or Arm B,120 g/m² bryostatin-1 given as a72 hour continuous infusion every 2 weeks.Although objective response was assessedusing standard NCIC CTG criteria,antitumour activity was assessed using amultivariate endpoint incorporating bothresponse (CR and PR) and early progression(PD at 8 weeks). Seventeen patientswere randomized to each arm. Results: Arm A was better tolerated with 86.7% of15 evaluable patients receiving 90%of planned dose intensity versus 76.5% of17 evaluable patients in Arm B. On Arm B,three patients experienced serious adverseevents and three patients had to be removedfrom protocol therapy due to toxicity. Themost common side effect was myalgia (33%grade 1–2 on Arm A versus 65% on Arm Bwith 5 patients experiencing grade 3 andone patient grade 4). Lethargy was morecommon on Arm A but more severe on Arm B. Other side effects such as nausea, diarrheaand headache were generally mild tomoderate in nature and occurred with asimilar frequency on both arms. Hematologicand biochemical toxicity were minimal. This trial was closed early because theprotocol-stopping rule was met based onlack of required responses and on thenumber of early progressions on both arms.No partial or complete responses were seen;3 patients randomized to Arm A had stabledisease (duration 9–24 weeks) as did 4patients (duration 10–38 weeks) randomizedto Arm B. Conclusion: Arm A wasbetter tolerated than Arm B. We concludethat bryostatin-1 has little efficacy inthe treatment of metastatic melanoma witheither of the schedules studied.     

Piritrexim in advanced,refractory carcinoma of the urothelium (E3896): a phase II trial of the Eastern Cooperative Oncology Group

This was a single-agent phase II clinicaltrial of the antifol piritrexim in patientswith advanced transitional cell carcinomaof the bladder. Methods: Patientswith previously-treated, advancedurothelial carcinoma were treated with oralpiritrexim at a dose of 25 mg three timesdaily for 5 consecutive days each week for3 consecutive weeks followed by a 1-weekrest period. Courses were repeated every28 days. Results: Thirty-fivepatients were enrolled in the study, with28 patients evaluable for survival andtoxicity and 27 evaluable for response. Toxicity: Myelosuppression was themajor dose-limiting toxicity, with WHOgrade 3/4 thrombocytopenia in 4 patients,granulocytopenia in 1 patient, and anemiain 3 patients. Grade 3 nonhematologictoxicity consisted of neuropathy in 5patients, hepatotoxicity in 2, nausea in 2,and 1 each with pulmonary toxicity andrash. Efficacy: Of the 27 patientsevaluable for response, 2 (7%) achieved anobjective response, lasting 112 and 142days, respectively. Conclusion: Piritrexim has minimal activity in patientswith previously treated transitional cellcarcinoma of the bladder, regardless ofprior exposure to methotrexate, and furtherevaluation of this compound in thisclinical setting is not warranted.     

Phase II evaluation of mitoxantrone in advanced pancreatic carcinoma: A Southwest Oncology Group study

Summary Patient with advanced adenocarcinoma of the pancreas and no prior chemotherapy were treated on a Phase II trial of mitoxantrone. Doses were adjusted for hepatic dysfunction as defined by bilirubin. Twenty-four patients with a bilirubin 1.5 mg% received mitoxantrone 12 mg/m² i.v. repeated every three weeks. Myelosuppression in the form of leukopenia was the major toxicity. There were no responses in twenty-four evaluable patients.