A Phase I trial of spirogermanium administered on a continuous infusion schedule

We have evaluated the toxicity of the antitumor agent spirogermanium on a schedule of continuous intravenous administration for periods up to five days. The doses tested were between 100 mg/m²/day and 500 mg/m²/day. Peripheral vein phlebitis occurred at all dose levels and was not relieved by addition of hydrocortisone or heparin to the infusion. No phlebitis occurred when the drug was administered through a central vein. The dose limiting toxicity of spirogermanium was neurologic, notably tremors and mental confusion. These problems became progressively more severe at doses above 250 mg/m²/day. There was no discernible bone marrow, renal or hepatic toxicity. One patient developed reversible interstitial pneumonitis. The recommended Phase II dose of spirogermanium is 200 mg/m²/day for five days, with the possibility of escalation in selected patients. Because spirogermanium is more toxic to tumor cells with prolonged exposure than with intermittent exposure, this schedule could be considered for Phase II trials, particularly in diseases thought to be especially sensitive such as ovarian and prostatic carcinoma or lymphomas.     

Hepatoma/merbarone

Summary Sixteen eligible patients with hepatocellular carcinoma, previously untreated, received merbarone 1000 mg/ m²/d for five consecutive days every 21 days. No complete or partial response to treatment was obtained. Seven patients had grade 4 granulocytopenia. One patient died with renal failure. Merbarone in this dose and schedule was ineffective in the treatment of hepatocellular carcinoma.     

Phase II study of ifosfamide and mesna in patients with previously-treated carcinoma of the cervix

Summary Thirty patients with advanced squamous carcinoma of the uterine cervix recurrent after radiotherapy or surgery and refractory to first-line chemotherapeutic agents were treated with ifosfamide in a dose of 1.2 grams/m² IV daily for five days every four weeks and Mesna 300 mg/m² IV every four hours for three doses daily for five days. One patient had an inadequate trial and two were inevaluable for response, leaving 27 patients evaluable for response. All but two patients had received prior radiotherapy and all but one prior cisplatin-based or cisplatin analog chemotherapy. Seventeen patients had prior surgery. All patients were Gynecologic Oncology Group performance status 0, 1, or 2. Partial responses were observed in three patients (11.1%), two with pelvic and one with extrapelvic disease. A 90% confidence interval for the true response rate is 4.5%–24.8%. Severe (grade 3 or 4) leukopenia and anemia were seen in nine and seven patients, respectively. Severe thrombocytopenia was not observed. Three patients had grade 3 or 4 neurotoxicity, and one had grade 3 renal impairment. Reversible alopecia was universal. This dose and schedule of ifosfamide and Mesna is active in patients with squamous carcinoma of the cervix failing platinum-based therapy. Phase II testing in untreated patients is currently underway.     

Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia

Summary Idarubicin (IDR) is a new analog of Daunorubicin (DNR) selected for clinical trials because of its outstanding activity in experimental leukemias of mice and in several experimental models when compared to DNR and Doxorubicin. This Phase I trial was designed to determine the maximal tolerated dose in adult patients with acute leukemia refractory to prior treatment, using intravenously (I.V.) daily treatments for 5 consecutive days.Eleven patients were entered in this study. The initial dose of IDR was 4 mg/m²/d × 5 I.V. The highest dose given was 8 mg/m²/d × 5 I.V. Dose limiting toxicity were gastrointestinal side effects at the 8 mg/m²/d × 5 level (mucositis-diarrhea). Antileukemic activity has been detected in acute non-lymphoblastic leukemia not pretreated with anthracyclines. For Phase II adult leukemia studies using this schedule, it is recommended that the IDR dose should be 7 mg/m²/d.     

Phase I trial of Uracil-Tegafur (UFT) plus oral leucovorin: 14-day schedule

We previously reported results of a Phase II trial of UFT [Taiho Pharmaceutical Ltd., Tokyo, Japan; (BMS-200604) Bristol-Myers Squibb, Princeton, NJ], an oral 4:1 molar concentration of uracil and tegafur, plus oral leucovorin for metastatic colorectal carcinoma (Pazdur et al, J. Clin. Oncol. 12:2296-2300, 1994]. Our results demonstrated that a 28-day schedule of this combination produced a response rate similar to that obtained with conventional intravenous fluorouracil (5-FU)-plus-leucovorin regimens but without the severe or life-threatening neutropenia or oral mucositis that complicates intravenous 5-FU regimens. The current Phase I trial examines the dose-limiting toxic effects and maximum tolerated dose of a 14-consecutive-day schedule of UFT plus oral leucovorin in 14 patients who had histologically proven cancer and had received prior chemotherapy. The daily UFT plus leucovorin dose was divided into three doses administered orally every 8 hours. In this study, the UFT dose was escalated while the leucovorin dose remained at 150 mg/day. Of the 14 patients, 4 were initially treated at the 350-mg/m²/day UFT level for 14 days without any dose-limiting toxic reactions. Subsequently, another 7 patients were treated at the 400-mg/m²/day level; grade 3 diarrhea developed in 3 of these 7 (with severe abdominal cramping in 2 cases and severe nausea and vomiting unresponsive to antiemetics in the third). To better define the starting dose for phase II studies, an additional 3 patients were treated at the 350-mg/m²/day dose level. Of the total 7 patients treated at 350 mg/m²/day, grade 3 toxic events (diarrhea) developed in 2 patients. Grade 1-2 toxic effects noted at this level included fatigue, stomatitis, skin rash, abdominal pain, nausea, and vomiting. Neither partial nor complete responses were observed in this trial. The maximum tolerated dose of this schedule is 350 mg/m²/day UFT plus 150 mg/day oral leucovorin. However, because of this schedule's inferior dose intensity compared with that of the 28-day schedule of UFT plus leucovorin, subsequent development of UFT in the United States has focused on the 28-day regimen.     

Phase-I trial of 4-demethoxydaunorubicin in acute leukaemias

Summary Eleven patients with heavily pretreated acute leukaemia were treated with 4-demethoxydaunorubicin. Dosages were escalated from 7 mg/m²/d to 15 mg/m²/d for 3 consecutive days. One patient achieved a partial remission and antitumor activity was seen in most other patients. Stomatitis was dose-limiting at 15 mg/m². Phase II trials are warranted and we propose a schedule of 12 mg/m²/d for 3 consecutive days.     

Phase I studies of trimetrexate using single and weekly dose schedules

Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, was shown to be more active than its analogue, Methotrexate, against murine and human tumor cell lines in vitro and in vivo. We conducted two sequential phase I studies using a single bolus injection of TMTX every 14 days (Schedule A) and a weekly × 3 schedule every 4–6 weeks (Schedule B). Twenty-seven patients were treated on Schedule A with a TMTX dose range of 5 mg/m² to 450 mg/m² and 23 patients were treated on Schedule B with a TMTX dose range of 50 mg/m² to 200 mg/m². The dose limiting toxicity was myelosuppression on both schedules. The development of hematological toxicity was highly variable at different dose levels and within the same patient at a particular dose level. The nadir of blood counts was reached by Day 8 to 10 on the single dose schedule with recovery by Day 14. On Schedule B, the nadir granulocyte count occurred on Day 14 while platelet count was generally lowest by Day 20; the blood counts usually recovered 7 to 10 days after the last dose. Other common side-effects includes skin toxicity and stomatitis which were worse on the weekly schedule. Less common toxicities included mild nausea and vomiting, diarrhea, and transient deterioration in renal and hepatic functions. The occurrence of toxicity was not related to the extent of prior treatment, liver metastases, or accumulation of third space fluids. Based on our results, we recommend a starting TMTX dose for Phase II studies of 200 mg/m² every 2 weeks or 100 mg/m² to 125 mg/m² on the weekly schedule.     

Phase I clinical study of nafazatrom

Nafazatrom, a synthetic pyrazolinone derivative, has been shown to have substantial antitumor activity in vitro and antitumor and antimetastatic activity in experimental animal systems. The drug has produced no substantial toxicity in preclinical studies and during limited human trials. A phase I clinical trial with this substance was performed at this institution. Nafazatrom was administered orally in a single daily dose. The initial starting dose was 30 mg/m² and, in the absence of toxicity, subsequent dose levels were reached after 100% escalation. Six patients were treated at each dose level. Forty-eight patients with various metastatic malignant tumors (mostly with melanoma, breast carcinoma, soft tissue sarcoma, renal cell carcinoma and colorectal carcinoma) were entered on this program. No objective remissions were observed. Twelve patients remained stable for periods in excess of 8 weeks. No consistent, substantial or dose-limiting toxicity was detected. The maximum tolerated dose was not reached, and dose escalation was stopped at 4,000 mg/m²/day as initially planned. With the oral preparation, within this dose range and at this schedule, nafazatrom has no antitumor or other biologic activity.     

Phase I study of DMP 840 in pediatric patients with refractory solid tumors

The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m² daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.     

Phase I study of DMP 840 in pediatric patients with refractory solid tumors

The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m² daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.     

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Summary Purpose: This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine. Experimental design: Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m²/day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h. Results: In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m²). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/ m² dose level. Objective evidence of clinical activity was observed in four patients. Conclusions: The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m²/day of 3-AP on days 2–5 given prior to cytarabine administered at a dose of 1,000 mg/m²/day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.     

Phase II study of low dose cyclophosphamide and intravenous interleukin-2 in metastatic renal cancer

Thirteen patients with metastatic renal cancer were treated in a phase II trial with interleukin-2, 21.6 million IU/m² intravenously daily for five days on two consecutive weeks, starting 3 days after the administration of low dose cyclophosphamide 350 mg/m² intravenously. Treatment cycles were repeated every 21 days. No responses were seen (95% Confidence Interval: 0–22%). The most common toxicities were fever, fatigue, hypotension, nausea/emesis, and myalgia/arthralgia. There were 11 episodes of Grade III toxicity including Grade III hypotension in 7 patients. Because of the significant toxicity and the lack of observed response, the study was discontinued. Cyclophosphamide and interleukin-2 at the dose and schedule used in this study has considerable toxicity and is unlikely to improve on response rates previously seen with other IL-2-based regimens in metastatic renal cancer.     

Difluorodeoxycytidine (dFdC) — gemcitabine: A phase I study

Summary Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5–90 mg/m² and 22, by 5 minute bolus at 30–150 mg/m². The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m² on the infusion schedule and 150 mg/m² on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.     

Phase II trial of ixabepilone,an epothilone B analog,given daily for three days every three weeks,in metastatic breast cancer

Summary Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m²/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m²/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m², 8 mg/m² and 10 mg/m² dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8–10 mg/m² daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.     

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m²/d × 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m²/d × 5. The recommended Phase II dose is 4.3 mg/m²/d × 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8–8.4 mg/m²/d × 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.     

Phase I Study of N1-N11-Diethylnorspermine (DENSPM) Administered TID for 6 Days in Patients with Advanced Malignancies

This was a dose escalation Phase 1 trial designed todetermine the maximum tolerated dose (MTD) and dose-limitingtoxicities (DLT) of DENSPM. Methods: Adult patientswith refractory solid tumors were treated with DENSPMadministered by intravenous infusion in 100 ml of normalsaline over 30 minutes. The daily dose of DENSPM was dividedinto three equal doses administered approximately every eighthours for six days. Courses were repeated every 28 days.Results: Twenty-eight patients were enrolled in thestudy. Dose levels of DENSPM explored were 25mg/m²/day (3 patients), 50 mg/m²/day (9patients), 60 mg/m²/day (5 patients), 75mg/m²/day (6 patients), 94 mg/m²/day (3patients) and 118 mg/m²/day (2 patients). The DLTfor DENSPM was central nervous system toxicity characterizedby aphasia, ataxia, dizziness, vertigo and slurred speechoccurring at dose levels 94 mg/m²/day, whichwas also the MTD. Safety: The most frequent drug-relatedadverse events were asthenia (9 patients), injection sitereaction (6 patients) and anemia (6 patients). One patient wasremoved from the study due to CNS toxicity. There were notreatment-related deaths. No trends were observed regardinghematologic toxicities, biochemical changes or changes invital signs. Efficacy: Nineteen of the 28 patients enrolled inthe study were assessed for response. No objective responseswere observed. Five patients had stable disease as the bestresponse to therapy. Conclusions: Because the DLT wasCNS and because of the relatively low doses that could besafely administered on this schedule as compared with aonce-a-day schedule, this regimen was not recommended forPhase 2.     

Phase I trial of edatrexate plus carboplatin in advanced solid tumors: amelioration of dose-limiting mucositis by ice chip cryotherapy

Purpose: Edatrexate (10-Edam) is a methotrexate analog with improved intracellular transport, polyglutamation, and antitumor activity compared to the parent compound. Edatrexate shows schedule-dependent synergism with platinum compounds in preclinical studies. We performed a phase I trial to determine toxicities and establish the maximum tolerated dose (MTD) of edatrexate in combination with carboplatin. Based on the short initial plasma half-life of edatrexate, prophylactic ice chip cryotherapy was used to reduce the severity of mucositis. Patients and methods: Forty-six chemotherapy-naive patients with advanced solid tumors were treated. Edatrexate was given weekly for 5 doses (50% on day 8), and then every other week, followed by carboplatin at a fixed dose of 350 mg/m² on day 1 and then every 4 weeks for 8 cycles. Edatrexate dose was increased at increments of 10 mg/m²/dose level beginning at 60 mg/m²/week (range 60–120 mg/m²). Results: All patients were assessable for toxicity and response analysis. The median number of cycles administered per patients was 4. This combination chemotherapy regimen was well tolerated. Using ice chip cryotherapy, no grade IV mucositis was observed. Grade III mucositis occurred in only 7/46 pts and was not dose-related. Protocol-defined dose-limiting toxicity occurred at a edatrexate dose level of 120 mg/m², yielding an MTD of 110 mg/m². Responding tumor types included non-small cell and small lung cancer, head and neck cancer, and bladder cancer. Conclusions: 1) This phase I study demonstrated the safety and tolerability of this edatrexate and carboplatin combination. 2) Dose-limiting mucositis did not occur allowing escalation of edatrexate dose above levels previously achieved with this edatrexate dose schedule. This was most likely a result of prophylactic ice chip cryotherapy. 3) An edatrexate dose of 110 mg/m² with ice chip cryotherapy is recommended for Phase II trials of this combination.     

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia

Summary Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m²/day to 130 mg/m²/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2 + months. Both patients were treated at a dose of 100 mg/m²/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.     

A Phase I trial of Cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin,CBDCA, JM-8) with a single dose every five week-schedule

Summary Carboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200–550 mg/m² every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m² Carboplatin, the median platelet nadir was 65 000/mm³. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50–155) ml/min and dropped to a median lowest creatinine clearance of 69 (23–171) ml/min on day four (p < 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42–155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m² every five weeks. A starting dose of 450 mg/m² seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200–500     

Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma

Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m² of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m² with a relatively large apparent volume of distribution at steady-state of 1012 l/m² indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.