Eligible patients were at least 18 years of age and had a histologically documented, advanced stage solid tumor that was refractory to standard therapy or for which no curative standard therapy was available. Other inclusion criteria included: Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; absolute neutrophil count ≥ 1,500/mm3, platelet count ≥ 100,000/μL; total bilirubin < 1.5 mg/dL; aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2 × the institutional upper limit of normal; serum creatinine ≤ 2.0 mg/dL; adequate left ventricular function (> 45% at rest); and willingness and ability to provide written informed consent.
Exclusion criteria included: lifetime cumulative doxorubicin exposure > 300 mg/m2; history of myocardial infarction, congestive heart failure, or clinically significant ventricular arrhythmias; ≤ 4 weeks since prior chemotherapy or radiation therapy; enrollment in a clinical trial using another anti-neoplastic or investigational agent given during the planned course of doxorubicin and MGd; pregnant or lactating women; history of porphyria (testing not required at screening); history of glucose-6-phosphate dehydrogenase (G6PD) deficiency (testing required at screening unless a prior test result was available); ≤ 14 days since ingesting multidrug resistant modulating drugs, such as cyclosporine; or an inability to complete specified follow-up assessments.
Each patient gave written informed consent, according to institutional and federal guidelines. The protocol was approved by the Institutional Review Boards at the University of Wisconsin, Madison, and at the University of Pittsburgh.
This was a multicenter single arm phase 1 trial designed to determine the effect of combining MGd and doxorubicin in patients with advanced malignancies. A paired-course design, in which every patient was treated with doxorubicin alone, with MGd alone, and with the combination, was chosen in order to compare the safety of each treatment and to assess whether MGd increased the toxicity of doxorubicin. Each patient served as their own control. Cycle 1 lasted 28 days, while subsequent cycles lasted 21 days. Six cycles of treatment, or treatment up to a lifetime cumulative dose of 450 mg/m2 doxorubin, were planned.
As shown in the , all patients received a single dose of MGd on day 1 of cycle 1 and doxorubicin on day 8 of cycle 1. Patients were divided into two groups (Groups A and B) after meeting eligibility criteria and prior to the initiation of therapy. Assignment to Groups A or B alternated between consecutive patients enrolled at a single center. Patients in Group A received 3 daily doses of MGd on days 8, 9, and 10 of cycle 1. The cycle 1 day 8 dose of MGd was given 4 hours after the start of the doxorubicin administration. Patients assigned to Group B received doxorubicin alone on day 8 of cycle 1. If no dose limiting toxicities (DLTs) occurred in cycle 1, then cycle 2 started on day 29. Treatments in cycle 2 were reversed. All patients received doxorubicin on day 1 of cycle 2. Patients in Group B then received 3 daily doses of MGd on days 1, 2, and 3 of cycle 2. The cycle 2, day 1 dose of MGd was given 4 hours after the start of the doxorubicin administration. Patients in Group A received only doxorubicin on day 1 of cycle 2. For all subsequent cycles (cycles 3 – 6), all patients (Groups A and B) received doxorubicin on day 1, followed by 3 daily doses of MGd on days 1, 2, and 3, with MGd given 4 hours after the start of the doxorubicin administration on day 1.
Treatment of Patients in Groups A and B
Adverse events were evaluated using the National Cancer Center (NCI) Common Toxicity Criteria (CTC), version 2.0.
Motexafin gadolinium was supplied by Pharmacyclics, Inc. (Sunnyvale, CA) in a solution containing 2.5 mg/mL MGd in 5% mannitol, USP. It was administered undiluted, at a volume calculated to supply the correct dosage, intravenously (IV) over 30 minutes, and within 8 hours after being drawn from the vial since it was formulated without preservatives. Injection was supplied in 50 mL vials. Doxorubicin hydrochloride for injection was supplied commercially, and was stored and prepared according to the manufacturer’s instructions. It was infused IV over 15 minutes. Patients were premedicated with standard antiemetics according to institutional guidelines and practice.
All blood counts must have met treatment criteria, and all significant adverse events must have resolved or adequately improved to grade 1 or less prior to proceeding to the next cycle of treatment. Cohorts of 3 to 6 patients were treated until the maximum tolerated dose (MTD) was established or until the highest intended dose level was treated. Cohorts of 3 patients were expanded to 6 upon the identification of a DLT. Further dose escalation could occur if no more DLTs were observed. Patients were evaluable for determination of DLTs only after they had received doxorubicin and at least one dose of MGd in combination treatment. The DLT assessment period extended through 21 days after the patient received the combination doxorubicin and MGd treatment (cycle 1 day 29 for Group A patients, and cycle 2 day 22 for Group B patients). The MTD was defined as the highest dose level at which 0 or 1 out of 6 evaluable patients experienced DLTs. Patients terminated from treatment for toxicity other than a defined DLT were replaced.
Dose limiting toxicities were judged to be related to protocol treatment and included: any grade 4 hematologic toxicity lasting ≥ 7 days, non-hematologic toxicity ≥ grade 3, other than nausea or vomiting; or ≥ grade 3 nausea or vomiting unresponsive to antiemetic therapy.
Patients were removed from protocol treatment for the occurrence of a DLT; disease progression; treatment delay ≥ 2 weeks for ANC ≤ 1500/mm3 or platelet count ≤ 100,000/μL; the finding of left ventricular ejection fraction at rest below 45% and decreased 10% (absolute change) compared with screening ejection fraction, or 15% decreased (absolute change) compared with screening ejection fraction if it was still within the normal range (> 45%); cumulative lifetime doxorubicin dose ≥ 450 mg/m2, or investigator’s discretion. Dose delays were specified in the protocol. Participants were followed for a minimum of 8 weeks following their termination from study treatment.
Pretreatment and follow-up studies
History, physical examination, weight, assessment of ECOG performance status, listing of concurrent medications, CBC, PT/INR, PTT, total bilirubin, AST, ALT, and serum creatinine were obtained from all patients at baseline to determine eligibility. Additional pre-registration studies included measurement of height, serum pregnancy testing for women of childbearing age, an ECG, G6PD determination, and a urinalysis. Patients with measurable disease had their tumor measurements assessed by RECIST criteria at baseline and at the end of every even-numbered cycle of treatment. All patients with responding tumors were required to have response confirmed with imaging 4 weeks after the first documented response. Patients also underwent assessment of left ventricular function at rest per MUGA scanning at baseline, after cycles 2 and 4 of treatment, and 2 months after the completion of cycle 6. A CBC and serum chemistries (ALT, AST, GGT, albumin, alkaline phosphatase, BUN, calcium, bicarbonate, chloride, potassium, sodium, glucose, lactate dehydrogenase, phosphorus, serum creatinine, total bilirubin, total cholesterol, total protein, and uric acid) were obtained on weekly (days 1, 8, and 15) through every cycle of treatment, on day 22 of cycle 1, and at follow-up visits at 1 and 2 months following completion of therapy. Additionally, serum troponin-I was drawn on days 1, 8, and 22 of cycle 1 and on days 1 and 15 of all subsequent cycles. Lastly, an ECG, serum troponin-I, and a urinalysis were obtained 2 months after completing protocol treatment.
All patients who received MGd were included in the safety analyses, which included extent of drug exposure, detailed summaries of deaths by time to death using Kaplan-Meier methods and by cause of death, detailed examination of adverse events, laboratory test results, and physical examination findings.
The primary objectives of this trial were to evaluate the safety and tolerability of MGd and doxorubicin in combination when administered to patients with advanced malignancies, and to determine the MTD and DLTs of this combination. Assessing the antitumor response rate using RECIST criteria served as a secondary objective.
The algorithm-based “3 by 3” design was chosen due to its practical simplicity. A dose level was considered intolerable if any of the following scenarios of DLT occurrences were observed: 2 or 3 of the first 3 patients experienced DLTs, or 1 of the first 3 patients experienced a DLT and so did 1 or more of the second 3 patients enrolled in that dose level. Probabilities for declaring a dose level intolerable, given various true occurrence rates of DLTs, were then calculated. For example, given a true DLT occurrence rate of 15%, the probability of declaring that dose level intolerable was 18.62%.