Vincristine with high-dose etoposide in advanced breast cancer: a phase II trial of the Piedmont Oncology Association

Vincristine (VCR) and etoposide (VP-16) have been shown to be synergistic in a murine model, and this combination was studied in a phase II trial. Eligibility required measurable disease, a performance status of 0–2, a life expectancy of 2 months, an interval of at least 3 weeks since the receipt of previous radiation therapy or chemotherapy and recovery from related toxicity, no prior treatment with VCR or VP-16, and no more than two prior chemotherapy regimens (only one for treatment of metastatic disease). Treatment consisted of 0.5 mg i.v. (bolus) VCR followed by 200 mg/m² VP-16 given over 2 h. Both drugs were given daily for 3 consecutive days every 3 weeks (total dose: VCR, 1.5 mg; VP-16, 600 mg/m²). A total of 18 patients with metastatic breast cancer were accured; 14 had adjuvant chemotherapy and 8 had chemotherapy for advanced disease. As judged by International Union Against Cancer (UICC) criteria, one complete response (CR) and three partial responses (PR) were obtained, for a CR+PR rate of 22% (95% confidence interval, 6%–48%). All responders had soft-tissue involvement only. Six patients had stable disease and 8 showed progression. The median time to treatment failure was 3.5 months, and the median survival from study entry was 8.3 months. The major toxicity was myelosuppression, with 9 patients (50%) experiencing a total WBC of <1,000/mm³. Grade 2–3 neurologic toxicity was noted in 6 patients (33%) and grade 3 nausea and vomiting was noted in 5 (28%). The combination of VCR and VP-16 is active in advanced breast cancer but is not convincingly superior to either of these agents used alone.Supported in part by grants CA-12197, CA-37378, and CA-45808 from the National Institutes of Health, National Cancer Institute, Bethesda, Maryland     

5-fluorouracil,leucovorin, hydroxyurea,and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study

Summary Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1–5,600 mg/m² 5-FU given i.v. daily by continuous infusion (c.i.) on days 1–5, escalating doses of cisplatin starting at 10 mg/m² daily given by c.i. on days 1–5, and involved-field XRT carried out on days 1–5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3–4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1–5, 400 mg/m² 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o. 4 h on days 1–5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m² daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m² daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors, particularly non-small-cell lung cancer and head and neck cancer. Due to the high incidence of severe cumulative toxicity, we recommend further use of this regimen only as part of a curative treatment strategy for patients presenting with locoregionally advanced solid tumors.Supported in part by an American Cancer Society Clinical Oncology Cancer Development Award (to M. J. R.) and by National Cancer Institute grant CA-14599-17     

Phase I clinical trial and human pharmacokinetics of 2,4-diamino-5-adamantyl-6-methyl pyrimidine ethane sulfonate (DAMP-ES): a lipid-soluble antifolate

Summary A phase I and pharmacokinetic study of a novel lipid-soluble antifolate, 2,4 diamino-5-adamanty-6-methyl pyrimidine ethane sulfonate (DAMP-ES) has been carried out on two schedules: I—dailyx5; II—24-h continuous infusion. In schedule I, doses of 10–90 mg/m² per day were evaluated. Dose-limiting toxicity was hematologic, but nausea and vomiting, skin rash, diarrhea, anorexia, alopecia, mucositis, and neurotoxicity were also noted. In schedule II, doses of 192 and 240 mg/m² were evaluated. Dose-limiting toxicity was neurotoxicity, but hematologic toxicity was also marked. Recommended starting doses for phase II studies are 75 mg/m² per day for 5 days or 192 mg/m² by continuous infusion for 24 h. Pharmacokinetic studies indicated a -phase plasma half-life of 12.4–24 h and a large and variable volume of distribution.Supported by USPHS Grant CA-21071 from the National Cancer Institute     

Phase I study of temozolomide combined with oral etoposide in children with malignant glial tumors

The treatment of children with malignant glioma remains challenging. The aim of this multicenter phase I study is to establish the recommended dose (RD) of the combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with relapsed or refractory malignant glioma and brainstem glioma at diagnosis. A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by a classical 3 + 3 design. Cohorts of patients were enrolled at 4 different levels: (1) TMZ 120 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (2) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (3) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10; (4) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–12. Therapy was administered in 28-day courses. A total of 118 courses were administered to 18 patients with a median age of 11.2 years. At dose level 1, none displayed toxicity. Of the 6 patients at dose level 2, 1 patient had dose limiting toxicity (DLT). None of the 3 patients at dose level 3 had DLT. At dose level 4, grade III/IV thrombocytopenia and neutropenia were observed in 2 out of the 6 patients enrolled. Therefore, the MTD was established at dose level 3. The RD for phase II trial in children with malignant glial is TMZ 150 mg/m² for 5 days and VP-16 50 mg/m² for 10 days every 28 days.     

Extremely prolonged continuous intraperitoneal infusion of cytosine arabinoside

Summary Intraperitoneal administration of ara-C produces a peritoneal/plasma concentration ratio of 330–1,000: In principle, optimal tumor-cell kill should be obtained when high ara-C concentrations ar maintained in the environment of the tumor for very long periods of time. A phase 1 study was undertaken to determine the maximum tolerated dose of ara-C that could be given as a continuous i. p. infusion for 3 weeks. A total of 14 patients with refractory malignancies were given 28 courses in the outpatient setting. Ara-C infusions were given using a portable programmable pump (Pancreatec Provider Model 2000). No significant side effects were observed in patients receiving 30 mg/m² per day (five courses) or 40 mg/m² per day ×21 days (seven courses). However, at a dose of 60 mg/m² per day, although 10/16 courses were tolerated for at least 1 week, only 3/16 attempted courses could be continued for the full 3 weeks. The dose-limiting toxicity was chemical peritonitis, which occurred during 7/16 courses at this dose level and required termination of therapy in 4 courses. Myelosuppression was also observed at this dose. There was a large variation in the ara-C and ara-U peritoneal concentrations both within and between patients. The mean peritoneal ara-C concentration increased nonlinearly with ara-C dose whereas the mean ara-U concentration decreased. This study establishes the feasibility and safety of giving a cell-cycle-specific drug intraperitoneally over an extremely prolonged period. For subsequent studies a dose of 40 mg/m² per day for 21 days is recommended.Supported in part by grants CA 35309 and CA 23100 from the National Institutes of Health; the UCSD General Clinical Research Center; grant RR00827 from the Division of Research Resources, National Institutes of Health; grant CH-368 from the American Cancer Society; a grant from the Upjohn Company Inc.; the Pancreatec Corporation; and a grant from the California Cancer Research Coordinating Committee. This work was conducted in part by the Clayton Foundation for Research, California Division. Drs. Howell and Zimm are Clayton Foundation investigators     

Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma

BackgroundThe prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient.MethodsA phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3 + 3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (2) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (3) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10; (4) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years.ResultsNone of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3.ConclusionThe recommended phase II dose in children is TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.     

GM-CSF,carboplatin, doxorubicin: a phase I study

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m², administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1–21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m², 325 mg/m² and 400 mg/m². At carboplatin 400 mg/m² and doxorubicin 60 mg/m², thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m², doxorubicin 60 mg/m², and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA-14028, CA-28862, CA-12213, CA-13612, CA-32102     

Clinical pharmacology of cytarabine in patients with acute myeloid leukemia: a Cancer and Leukemia Group B study

The pharmacokinetics of cytarabine (ara-C) were determined in 265 patients with acute myeloid leukemia (AML) receiving ara-C (200 mg/m² per day for 7 days as a continuous infusion) and daunorubicin during induction therapy. The mean (standard deviation) ara-C concentration at steady-state (Css) and systemic clearance (Cl) were 0.30 (0.13) M and 134 (71) l/h per m² respectively. Males had a significantly faster ara-C Cl (139 vs 131 l/h per m²,P=0.025) than females. Significant correlations were noted between ara-C Cl and the pretreatment, peripheral white blood cell count (P=0.005) and pretreatment blast count (P=0.020). No significant differences in ara-C Css or Cl were noted in patients achieving complete remission compared with those failing therapy (P=0.315,P=0.344, respectively). No significant correlations were observed between ara-C pharmacokinetic parameters and several indices of patient toxicity. Our findings indicate that variability in ara-C disposition in plasma at this dosage level does not correlate with remission status or toxicity in patients with AML receiving initial induction therapy with ara-C and daunorubicin.This study was supported in part by grants from the National Cancer Institute (CA-03927, CA-37027, CA-59518, CA-47577, CA-32291, CA-07968, CA-16450, CA-16450, CA-26806, CA-47545, CA-12197, and CA-41287), the Upjohn Company, and the Coleman Leukemia Research Fund     

Phase I study of high-dose cisplatin,ifosfamide, and etoposide

To test the feasibility of a regimen of high-dose cisplatin, ifosfamide, and etoposide (VP-16; VIPP regimen), we registered 15 patients with advanced non-small-cell lung cancer in a phase I trial of the Northern California Oncology Group. One cycle of treatment consisted of high-dose cisplatin given at 100 mg/m² i.v. on days 1 and 8, VP-16 given at 60–75 mg/m² i.v. on days 1–3, plus ifosfamide given at 1.0–1.2 g/m² i.v. on days 1–3; cycles were repeated every 28 days. There were 13 men and 2 women; the median age was 59 years (range, 47–72 years). The median Karnofsky performance status (KPS) was 90 (range, 70–100). All patients were assessable for toxicity and response. The median number of cycles delivered per patient was two (range, one to four). Hematologic toxicity was dose-limiting and required de-escalation of the ifosfamide and VP-16 doses. Ten patients developed a white blood count of <1000/mm³ and seven patients developed a platelet count of <50,000/mm³. The duration of cytopenia increased progressively with each subsequent cycle of therapy. Two patients required antibiotics for neutropenic fever with documented infections (pneumonia, bacteremia). Seven patients received red blood cell transfusions for a hemoglobin level of <8 gm/dl. Grade III or IV non-hematologic toxicities were uncommon and involved one patient each with grade 3 ototoxicity and grade 3 neurotoxicity. Five patients developed laboratory evidence of renal salt wasting. The overall response rate was 33% (5/15) with a complete response being achieved by two patients (13%) and a partial response being attained by three (20%). The overall median survival was 44 weeks. We conclude that although this regimen demonstrated activity, hematologic toxicity limited its use in the palliative treatment of non-small-cell lung cancer. Using hemopoietic growth-factor support to permit dose escalation, this schedule of VIPP may be of interest in a number of different chemotherapy-sensitive tumor types.     

Phase I clinical trial of fludarabine phosphate (F-ara-AMP)

Summary F-Ara-AMP (fludarabine phosphate) is an adenosine analogue that is resistant to deamination; it is a more potent cytotoxic compound than ara-A in experimental tumor systems. F-Ara-AMP was given by continuous IV infusion over 5 days once every 4 weeks to 27 evaluable adult patients with advanced cancer. The median Karnofsky performance status was 70% (range 50%–90%), and the median age was 58 years (range 41–74). In addition to adequate blood counts, a creatinine clearance of at least 60 ml/min was required. The initial dose level was 35 mg/m²/day. Dose-limiting myelosuppression was seen in the first patient. Subsequent patients were treated at lower doses. Myelosuppression was the only major toxicity. Leukopenia was generally more prominent than thrombocytopenia, but 2 patients experienced prolonged thrombocytopenia which prevented further therapy. Nausea was minimal, and neither renal nor neurologic toxicity was encountered. In patients with good renal function a dose of 25 mg/m²/day can be safely administered. However, because of apparent cumulative myelosuppressive effects a lower dose is more appropriate for patients who have had extensive prior chemotherapy or radiotherapy.Supported by CCPP grant CA-05826 and Contract NO1-CM-27546 from the National Cancer Institute, National Institutes of Health, Bethesda, Md. The content of this paper was presented in part at the 76^th meeting of the American Association for Cancer Research, Toronto, 1984     

7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin: mechanism of resistance and clinical trials

The camptothecin derivative 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin (CPT-11) has attracted the attention of clinicians because of its high antitumor activity against refractory solid cancers. We established two CPT-11-resistant cell lines, a non-small-cell lung-cancer cell line (PC-7/CPT-11) from the parental PC-7 line and an ovarian cancer cell line (HAC-2/CPT-11) from the parental HAC-2 line. The mechanisms of resistance to CPT-11 in PC-7/CPT-11 cells were reduced conversion of CPT-11 to its active metabolite SN-38 and point mutation of topoisomerase I. Those in HAC-2/CPT-11 cells were reduction of topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase I inhibitors. No point mutation of the topoisomerase was observed in HAC-2/CPT-11 cells. We conducted two phase I trials using CPT-11 in combination with other anticancer agents. One was a phase I trial of CPT-11 and cisplatin given with a fixed dose of vindesine to patients with advanced non-small-cell lung-cancer and the other was a phase I study on a topoisomerase-targeting combination of CPT-11 and etoposide (VP-16) in patients with various malignant solid tumors. The results of the first trial indicated that the recommended dose of CPT-11 for phase II studies was 80 mg/m² combined with 3 mg/m² vindesine on days 1 and 8 and 60 mg/m² cisplatin on day 1. In the second trial, the recommended dose of CPT-11/VP-16 given with recombinant granulocyte colony-stimulating factor (on days 4–17) was found to be 60/60 mg/m² In both trials, diarrhea and granulocytopenia were considered to be dose-limiting toxicities.Paper presented at the Topoisomerase Inhibitors Conference, University of Maryland Cancer Center, 27–30 October 1993, Monterey, California, USA. Supported in part by Bristol Myers Oncology Division     

Clinical and cell kinetic studies of the effects of the epipodophyllotoxin VP16-213 during therapy of refractory acute nonlymphocytic leukemia

Summary After induction failure or relapse on primary therapy, acute nonlymphocytic leukemia (ANLL) has historically been highly resistant to reinduction chemotherapy. In order to evaluate a new drug combination for this condition, 24 children and young adults with ANLL failing to attain first remission [5] or in relapse [19] were treated with VP16-213 plus 5-azacytidine (5AZ). Each patient had previously received combination chemotherapy with several antileukemic agents, including anthracyclines and cytosine arabinoside. These patients received 5-day courses of VP16-213 (200 mg/m²) daily x 3 days, followed immediately by 5AZ (300 mg/m²) daily x 2 days, repeated every 1–2 days until the bone marrow became hypoplastic. After 2–4 courses, 19 patients demonstrated an objective anti-leukemic effect by achieving marrow hipoplasia without evidence of blasts. Eleven of these (11/24=46%) achieved complete remission after a median time of 45 days from the initiation of therapy, making this combination of VP16-213 and 5AZ the most active regiment we have tested for ANLL in relapse. In order to determine the effects of VP16-213 on leukemic blast proliferation in vivo, serial bone marrow aspirates were studied in eight of these children. VP16-213 200 mg/m² IV was given daily x 3 days, and the mitotic index, labeling index and fractions of cells in G₀/G₁, S and G₂+M by flow cytometric measurement of DNA content were determined. Bone marrow samples were obtained before, 4 h and 20–24 h after the third dose in all patients, and 20–24 h after the third dose in six of the patients. The cytokinetic studies 4 h after the first dose of VP16-213 consistently showed a G₂ phase arrest of the bone marrow myeloblasts, indicating uptake of the drug and production of the same cell kinetic lesion which has been shown for cells treated with VP16-213 in vitro. In each patient studied 24 h after the third drug dose, there was a decrease in the fraction of cells in S phase compared to the pretreatment study (median decrease 56%, range 24–67%). The blast count per ml of marrow decreased by a median of 84% (range 72–91%) over this same interval. The observed decrease of fraction of cells in S phase after three doses of the drug suggests selective kill of cells in S compared to G₀/G₁. We conclude that the activity of VP16-213 against ANLL blasts can be demonstrated in vivo by the production of G₂ phase arrest and reduction of marrow blast count with findings consistent with increased cytotoxicity for cells in S and G₂ phase of the cell cycle. In addition, this intensive combination of VP16-213 and 5AZ has shown clear evidence of effectiveness in patients with refractory ANLL, and thus may be useful during initial therapy.Supported in part by Public Health Service grants CA-21765, CA-20180, and CA-15956 from the National Cancer Institute, National Institutes of Health, and Department of Health, Education and Welfare, and by ALSAC     

Weekly docetaxel in minimally pretreated cancer patients: A dose-escalation study focused on feasibility and cumulative toxicity of long-term administration

Background: Docetaxel is an agent with impressive clinical activity but a rather poor profile of toxicity when given every three weeks. Therefore, optimisation of its clinical use is highly warranted. This is a dose-escalation study of weekly docetaxel particularly focused on the feasibility of long-term administration and characterisation of cumulative toxicity.Patients and methods: Twenty-six patients (11 female/15 male, median age 56, range 23–73) were treated over the range of 25–50 mg/m²/week. Dose-limiting toxicity for this schedule was defined as any grade >2 antiproliferative toxic effect resulting in a >2-week delay for re-administration of the drug, or any grade >2 organ-specific toxicity. Patients were monitored clinically and electrophysiologically for neurotoxicity. No prolonged corticosteroid co-medication or prophylactic haematopoietic growth factors were given.Results: A median/mean number of 8.5/8.7 consecutive weekly courses were given per patient. The maximum tolerated dose that prevented on-schedule administration of the drug was 50 mg/m². The main cumulative toxicities were a mild fluid retention and dacryorrhea which became evident as the number of treatment courses increased. Grade 2 alopecia and fatigue were observed only at 45 mg/m² and higher. Activity was seen at all of the dose levels studied.Conclusions: Long-term weekly administration of docetaxel is feasible at doses up to 45 mg/m²/week with acceptable toxicity. Further clinical evaluation is justified at this schedule and 40 mg/m²/week of docetaxel is proposed for phase II studies as an active dose with minimal toxicity.     

A phase I trial of continuous infusion VP16-213 (Etoposide)

Summary Since there appears to be a schedule dose relationship for VP16-213, the current dose seeking study of 5 day continuous infusion was initiated. Patients not candidates for other treatments were started at 75 mg/m²/dayx5. Eight patients had prior chemotherapy, eight had radiotherapy plus chemotherapy and one patient had prior interferon. The median age was 53 (range 23–65) and the median performance status was 60 (range 50–90). Seventeen patients received 20 courses; two at 75 mg/m²/day, seven at 100 mg/m²/day, ten at 125 mg/m²/day, and six at 150 mg/m²/day. The major toxicity was hematologic and median WBC count nadirs (ranges) were respectively: 3.5 (2.3–4.7)x10³/l, 1.6 (0.2–3.4)x10³/l, 2.4 (0.1–3.6)x10³/l, 0.4(<0.1–0.7)10³/l. Platelet count nadirs were respectively: 150, 78 (20–189), 138 (26–326), 16 (9–88)x10³/l. The median days to WBC nadir and recovery and did not vary with dose and were 15 (9–21) and 24 (19–38) respectively. Median days to platelet count nadir were 12 (10–29) and recovery 24 (20–38) and did not vary with dose. Non-hematologic toxicities included mild nausea and vomiting, mild mucositis on six courses, diarrhea with two courses and fever during granulocytopenia during seven courses. Three patients manifested evidence of myocardial disease two with infarction and one with congestive failure during treatment. Two patients showed objective evidence of tumor regression, one patient with seminoma and one patient with renal cell carcinoma. The latter response was short. The current studies demonstrate that high dose continuous infusion VP16-213 is tolerable with acceptable toxicity using doses up to 125 mg/m²/day (625 mg/m² over 5 days).This investigation was supported in part by PHS grant number 1P50CA32107-1 Awarded by the National Cancer Institute, DHHS     

Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea

Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorouracil (5-FU), can be converted in a single step to fluorodeoxyuridine monophosphate (FdUMP), which binds covalently to thymidylate synthase (TS). Ribonucleotide reductase, an obligatory enzyme in the synthesis of deoxynucleotides, can be inhibited by hydroxyurea. Recognizing the well-established synergism between 5-FU and folinic acid (leucovorin), we hypothesized that the simultaneous administration of FUdR, leucovorin, and hydroxyurea might afford more effective inhibition of TS. Thirty-six patients with neoplastic disease considered refractory to standard therapy were entered into this phase I protocol. Treatment was administered on days 1 through 5 of a 28-day cycle and consisted of folinic acid (500 mg m^–2 day^–1) and FUdR at escalating doses of 0.1, 0.15, or 0.2 mg kg^–1 day^–1 both administered by continuous i.v. infusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 2500 mg in 500-mg increments. The hydroxyurea and FUdR levels were escalated in a sequential fashion. The majority of patients had refractory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 2000 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the 18 patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuous infusions of FUdR and high-dose folinic acid are combined with oral hydroxyurea, effects that are consistent with the observed toxicities for FUdR when administered alone or in combination with leucovorin.Supported, in part, by Cancer Center Core Support Grant CA-33572 from the National Cancer Institute     

A phase I trial of concomitant chemoradiotherapy with cisplatin dose intensification and granulocyte-colony stimulating factor support for advanced malignancies of the chest

Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results.Purpose: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy.Methods: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1–5 of weeks 1–3 and no treatment in week 4. When dose-limiting neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7).Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m² in weeks 1 and 2, IFN 5 million Units (MU)/m² per day on days 1–5 in week 1, 5-FU 800 mg/m² per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m² during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m² per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m² per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field.Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m² week 1, and 100 mg/m² week 2, IFN 2.5 MU, HU 500 mg every 12 h×11 and 5-FU 800 mg/m² per day with single fraction radiotherapy during weeks 1–3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.Presented at the International Association for the Study of Lung Cancer Workshop on Non-Small Cell Lung Cancer, Bruges, Belgium, August, 1993     

Phase I-II parallel study of docetaxel on a bimonthly schedule in refractory metastatic breast carcinoma

Background. The 3-week schedule with docetaxel (DTC) 75–100 mg/m² is associated with severe neutropenia, gastro-intestinal side-effects and fluid retention in a significant proportion of patients, which may be of concern in more elderly or poor performance status patients. A phase I–II trial was carried out to test the feasibility and the activity of a new bimonthly schedule of DCT. Patients and methods. The trial included a phase I study which aimed at the identification of dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of DCT on a bimonthly schedule. The first group of three patients received DCT 40 mg/m², and in absence of DLT, DCT dosage was escalated by 10 mg/m²/cycle until DLT was reached. In the phase II study, patients were randomized to receive: (a) standard 3-weekly DCT at the dose of 75 mg/m² (calibration arm); or (b) bimonthly schedule with DCT at the dose recommended in the phase I study. All patients were pretreated with chemotherapy, mostly anthracycline-based regimens, for advanced/metastatic disease. Analysis of response rates, toxicity, and dose-intensity were the main aims of the study. Results. The DLT was represented by severe myelosuppression which was recorded in all patients treated at 70 mg/m² dose level. Therefore, the MTD was 60 mg/m² on a bimonthly schedule. However, the dose recommended for the phase II trial was 50 mg/m², because no difference in delivered dose-intesity was seen between the 50 and 60 mg/m² dose levels, and the latter dosage was still associated with grade 3 neutropenia in most patients. The parallel phase II study showed that the bimonthly schedule of DCT (50 mg/m²) allows to deliver the same dose-intensity of DCT 75 mg/m² every 3 weeks. Grade 3–4 side-effects were rather infrequent in patients treated with the bimonthly schedule. Overall response rate (ORR) was 41 and 44% for the DCT 50 mg/m² bimonthly and the DCT 75 mg/m² every 3 weeks, respectively. Conclusions. Data achieved in the phase I part of the study showed that DCT 50 mg/m² every 15 days is the recommended dose for phase II studies, while results achieved in the phase II trial suggest that DCT 50 mg/m² in a bimonthly schedule is active as second-line chemotherapy for MBC being able to induce an ORR in the range reported for DCT 75–100 mg/m² every 3 weeks. The bimonthly schedule is, however, associated with relatively low toxicity. This characteristic may render the bimonthly schedule particularly attractive for future phase II trials of DCT in combination with other antineoplastic agents.     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

Phase I/II trial of topotecan given as continuous infusion in combination with oxaliplatin in 5-FU-pretreated patients with colorectal cancer

Background Oxaliplatin and topotecan are novel options for a variety of neoplasms. Topotecan has shown fewer side effects and higher efficacy when given as a continuous i.v. infusion compared to single doses, but this regimen has not yet been combined with oxaliplatin.Patients and methods This phase I/II trial was designed to establish the dose-limiting toxicity of a combination of oxaliplatin (85–130 mg/m² on day 1) and a continuous infusion of topotecan (initial 0.9 mg/m² over 72–120 h). Eligible patients with metastatic colorectal cancer had progressive disease during, or within 12 weeks after, palliative fluoropyrimidine-based chemotherapy or in whom intolerable 5-FU toxicity had developed.Results The study included 21 patients. Subjectively the treatment was well tolerated but haematological toxicity was observed with the initial treatment schedule of oxaliplatin 85 mg/m² on day 1 and topotecan 0.9 mg/m² on days 1–5. Reducing topotecan to 0.9 mg/m² on days 1–3 resulted also in acceptable haematological toxicity. In patients completing three or more therapy cycles, median progression-free survival was 5 months, and 50% had stable disease or showed a partial response.Conclusion The recommended dose of this combination for further testing is oxaliplatin 85 mg/m² on day 1 and topotecan 0.9 mg/m² per day as a continuous infusion on days 1–3.Dr. Hubert Szélenyi, born 11 January 1965, died in the prime of life on 29 August 2002. We are deeply saddened by the loss of an excellent physician, accomplished scientist and admirable and warm-hearted friend and colleague. He had essentially designed and developed this study, and we decided to finish it in compliance with his intentions.     

Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours

Background Zosuquidar (LY335979) is an oral P-glycoprotein modulator. This phase I study was designed to determine the maximum tolerated dose (MTD) of zosuquidar in combination with vinorelbine. The effects of zosuquidar on vinorelbine pharmacokinetics were also examined.Design Patients with advanced solid tumours were treated with escalating doses of zosuquidar administered every 8–12 h on days 7–9 and 14–16 during cycle 1 then days 0–2, 7–9, and 14–16 from cycle 2 onwards, with vinorelbine 22.5–30 mg/m² IV on days 1, 8 and 15 every 28 days.Results Of 21 patients registered, 19 were treated at four dose levels (zosuquidar 100–300 mg/m²). Two patients had prolonged and febrile neutropenia at the second dose level resulting in a reduction of the dose of vinorelbine in subsequent dose levels. There was another patient with dose-limiting febrile neutropenia at dose level four which resulted in the expansion of the dose level three. Eight patients had stable disease and no objective responses were seen. Vinorelbine pharmacokinetic studies showed reduced clearance when given with zosuquidar.Conclusions The MTD was zosuquidar 300 mg/m² orally every 12 h for 3 days weekly for 3 weeks with vinorelbine 22.5 mg/m² IV weekly for 3 weeks every 28 days. Zosuquidar may inhibit vinorelbine clearance to a modest degree.