Purpose: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk).

Experimental Design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design.

Results: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m2. Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m2, with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose.

Conclusion: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study. Clin Cancer Res; 20(8); 2205–14. ©2014 AACR.

This article is featured in Highlights of This Issue, p. 2017

Translational Relevance

Lurbinectedin (PM01183) is a novel synthetic tetrahydroisoquinoline with broad antitumor activity in vitro. This first-in-human study defined 7.0 mg flat dose as the phase II recommended dose with PM01183 administered as 1-hour intravenous infusion every 3 weeks. The primary toxicity at the recommended dose was myelosuppression, mainly consisting of nonfebrile grade 4 neutropenia in 40% of patients. Despite this severe neutropenia, episodes were transient and shortlasting, and had limited consequences on treatment schedule. Other common PM01183-related adverse events at the recommended dose were mild/moderate fatigue, nausea, and vomiting. The pharmacokinetic profile showed dose proportionality within the dose range explored and no drug accumulation between cycles. One confirmed partial response as per Response Evaluation Criteria in Solid Tumors v.1.0 with tumor marker normalization was found in a previously refractory pancreatic cancer patient. Prolonged disease stabilization with evidence of tumor shrinkage occurred in three patients with soft-tissue synovial sarcomas and malignant melanoma.

Lurbinectedin (PM01183; PharmaMar) is a novel synthetic tetrahydroisoquinoline structurally related to ecteinascidins (1, 2). PM01183 showed in vitro broad antitumor activity against several representative human cell lines, with half-maximal inhibitory growth concentrations (IG50) within the picomolar range (3). In vivo studies showed significant growth inhibition of a wide variety of human cancer xenografts in athymic mice (3).

PM01183 binds covalently to the DNA minor groove, forming adducts that are capable of inducing mainly double-strand breaks, but also interfering with normal protein synthesis machinery at the mRNA level. Accumulation of DNA damage delays progression through the S–G2 phase of the cell cycle and ultimately triggers apoptotic cell death (4–7).

Preclinical toxicology studies revealed that PM01183 primarily caused myelosuppression, inducing anemia, bone marrow depletion, and atrophy of the lymphoid system. Other toxicities were species dependent, such as hepatotoxicity, which was not observed in beagle dogs. Effects tended to be dose dependent and transient, although the maximum-tolerated dose (MTD), when normalized to body surface area (BSA), differed significantly from one species to another. The female Sprague-Dawley rat was the most sensitive of all species tested, with a MTD of 0.18 mg/m2. As recommended by the International Conference of Harmonization (ICH; both European Medicines Agency and U.S. Food and Drug Administration) guidelines (8–10), approximately one tenth of this dose was selected as a safe starting dose for this first-in-human study.

Given its broad in vitro activity against human solid tumor cell lines and its in vivo activity in xenografted human tumors, together with its acceptable and predictable preclinical toxicology profile, an accelerated titration design was used in this first-in-human, phase I clinical trial to spare most patients from being treated at potentially subclinically inactive doses. The trial was aimed at identifying the dose-limiting toxicities (DLT) and determining the MTD and the recommended dose for phase II trials when PM01183 is administered intravenously over one hour every 3 weeks (q3wk) to patients with advanced solid tumors. The pharmacokinetic profile, safety, and preliminary antitumor activity were secondary objectives.

The study was conducted at the Vall d'Hebron University Hospital (Barcelona, Spain) and the University of Chicago (Chicago, IL) in accordance with the ICH Good Clinical Practice guidelines, and was approved by the respective Research Ethics Committees. Written informed consent was obtained before any procedure. The study is registered at ClinicalTrials.gov as NCT00877474.

Eligibility criteria

Eligible patients were ages ≥18 years with histologically proven advanced solid tumor refractory to standard therapy or with no such therapy available; had recovered from previous toxicities to grade ≤1 (excluding alopecia); and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and adequate bone marrow, hepatic, and renal function.

Exclusion criteria

Patients were excluded if they had received any other antitumor therapy within 3 weeks before inclusion, could achieve tumor-free survival or significant palliation by surgery, had progressive central nervous system metastases, were immunocompromised, were pregnant or lactating women, or had increased cardiac risk, significant neurologic or psychiatric disorders, active infection, significant non-neoplastic liver disease, or known hypersensitivity to any drug component.

Study treatment

PM01183 was supplied as a powder concentrate in 0.2 and 1.0 mg vials and reconstituted in 1 and 2 mL of sterile water for injection, respectively. The reconstituted solution was further diluted with 5% dextrose solution for infusion (0.2 mg vials) or either 5% glucose or 0.9% sodium chloride solution for infusion (1.0 mg vials). Antiemetic prophylaxis was not allowed before nausea and/or vomiting were determined to be treatment-related toxicities. Intrapatient dose escalation was not allowed under any circumstances. Dose levels were rounded to integer numbers if appropriate. Treatment was administered until disease progression, unacceptable toxicity, treatment delay >2 weeks for any reason (except in cases of obvious patient benefit), intercurrent illness that precluded continuation of the study, patient refusal, and/or noncompliance with study requirements.

Dose escalation

The starting dose chosen for this first-in-human study was 0.02 mg/m2. According to the accelerated dose-escalation design defined for this study, cohorts of at least one evaluable patient were assigned to each dose level and dose escalation proceeded at 100% dose increments, as previously used (11). In the event of clinically relevant grade ≥2 toxicities in any patient in any cohort during the accelerated titration phase, cohorts of at least three patients were to be treated and up to 50% dose escalation was allowed if no DLTs had occurred. Once a DLT was observed at any dose level, the design switched to a classical 3+3 design with further dose increases limited at a maximum of 25% increments, provided the MTD had not been reached yet.

Dose-limiting toxicities

DLTs were defined as: grade 4 neutropenia for >7 days or with fever (≥38.5°C), sepsis or severe infection, grade 4 thrombocytopenia, any grade ≥3 nonhematologic toxicity (excluding nausea/vomiting without antiemetic treatment, grade 3 diarrhea lasting <24 hours without treatment, grade 3 asthenia for <5 days, hypersensitivity reactions, and nonclinically relevant isolated biochemical abnormalities), >2-week delay in a subsequent PM01183 administration due to toxicity. Following the European Medicines Agency's Guidance on the Evaluation of Anticancer Medicinal Products in Man (CPMP/EWP/205/95), the MTD was prospectively defined as the lowest dose level explored at which one third or more of patients experienced DLTs; and the recommended dose was the highest dose level explored below the MTD with less than one third of patients experiencing DLTs in cycle 1.

Study assessments

At baseline, the patient's relevant medical history was determined. A complete physical examination was conducted, including the ECOG performance status score assessment both at baseline and at the beginning of each treatment cycle. Hematology tests [differential white blood cells (WBC), hemoglobin, and platelets] and some biochemistry tests (liver function tests, creatinine, serum electrolytes, glucose, blood urea nitrogen, uric acid, and creatine phosphokinase; CPK) were conducted at baseline and weekly throughout the treatment period. Other biochemistry tests (total protein, albumin, α1-acid glycoprotein, and C-reactive protein), coagulation tests, and urinalyses were performed at baseline and at the beginning of each treatment cycle. If any grade ≥3 laboratory abnormalities occurred, the hematologic counts or appropriate chemistry test(s) were repeated at least every 2 to 3 days until recovery. Electrocardiograms and left ventricular ejection fraction assessments were conducted at baseline, and repeated while on treatment only if clinically indicated. All adverse events and laboratory variables were assessed at baseline and during treatment. Antitumor activity was evaluated every 2 cycles (6 weeks).

Pharmacokinetic analyses

Blood samples were collected on day 1 of cycle 1 at predose, 5 minutes before infusion end, and between 0.25 and 168 hours postinfusion. In addition, blood samples were also collected following the same sampling on day 1 of cycle 2 during cohort expansion at the recommended dose. Samples were centrifuged at 2500 × g for 15 minutes at 4°C and plasma was separated and stored at −20°C until analysis. The urine produced during the first day of treatment was collected and a 20-mL aliquot was stored at −20°C until analysis. Concentrations of PM01183 were determined using a liquid chromatography system coupled with electrospray ionization liquid chromatography/tandem mass spectrometry method. The limit of quantitation was 0.05 ng/mL.

Statistical analysis

Patient accrual was presented descriptively. Demographics and baseline characteristics were summarized for all patients and analyzed by dose. Continuous variables were presented with summary statistics (mean, median, and range) and categorical variables in frequency tables. Treatment exposure, delays, and reductions were evaluated using counts, percentages, and detailed listings. The total number of included patients, the number of patients evaluable for DLTs, and the number of patients with any DLT were summarized by dose. Descriptive statistics were used for the evaluation of safety. The incidence and grade of adverse events and laboratory abnormalities were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0 (12) and the events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) v.11. Antitumor activity was evaluated as per the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 (13). Response rates were characterized using descriptive statistics. Time-related parameters were analyzed according to the Kaplan–Meier method. SAS v9.2 (SAS Institute Inc) was used to generate these outputs. Noncompartmental pharmacokinetic parameters were calculated using WinNonLin v.5.2 (Pharsight). All individual pharmacokinetic parameters were tabulated and summarized. Categorical and continuous covariates were explored against pharmacokinetic parameters using the PROC MIXED procedure under SAS v.8.2 (SAS Institute Inc). Ninety-five percent confidence intervals for the slope and p test with a level of significance of 0.05 were calculated to detect differences and correlations. Pharmacokinetic graphics were performed using R v.2.15.0 (R Development Core Team) and the plotting package ggplot2 v.0.9.3 (14). The interindividual coefficient of variation (CV) was calculated as the ratio of the SD to the mean for the entire population. Similarly, the intraindividual coefficient of variation was determined for each patient.

Patient characteristics and treatment

Thirty-one patients were included between March 2009 and September 2010; patient characteristics are shown in Table 1.

Table 1.

Baseline characteristics of patients (n = 31)

RD (n = 15)Total (n = 31)
Gender 
 Male 8 (53%) 21 (68%) 
 Female 7 (47%) 10 (32%) 
Median age (range; y) 59 (21–75) 61 (21–77) 
ECOG performance status 
 0 7 (47%) 14 (45%) 
 1 8 (53%) 17 (55%) 
Median albumin (range; g/dL) 4.0 (3.4–4.7) 4.0 (3.3–4.7) 
Median hemoglobin (range; g/dL) 12.6 (9.7–14.5) 12.8 (9.1–15.7) 
No. of patients with LDH > ULN 6 (43%) 15 (50%) 
 Median LDH (range; x ULN)a 1.2 (1.0–3.8) 1.3 (1.0–3.8) 
Primary tumor 
 Colorectal cancer 7 (47%) 17 (55%) 
 Pancreatic cancer 3 (20%) 4 (13%) 
 Biliary tract cancer .— 2 (7%) 
 Soft tissue sarcoma 1 (7%) 2 (7%) 
 Otherb 4 (27%) 6 (19%) 
Median number of metastatic sites (range) 3 (1–5) 3 (1–5) 
Sites of disease 
 Visceral 1 (7%) 8 (26%) 
 Nonvisceral 2 (13%) 3 (10%) 
 Both 12 (80%) 20 (65%) 
Prior treatment 
 Chemotherapy 15 (100%) 31 (100%) 
 Biological therapy 10 (67%) 22 (71%) 
 Radiotherapy 8 (53%) 16 (52%) 
 Investigational therapy 4 (27%) 9 (29%) 
Number of prior chemotherapy-containing regimens 
 Median 
 ≤2 5 (33%) 12 (39%) 
 4 or more 5 (33%) 10 (32%) 
RD (n = 15)Total (n = 31)
Gender 
 Male 8 (53%) 21 (68%) 
 Female 7 (47%) 10 (32%) 
Median age (range; y) 59 (21–75) 61 (21–77) 
ECOG performance status 
 0 7 (47%) 14 (45%) 
 1 8 (53%) 17 (55%) 
Median albumin (range; g/dL) 4.0 (3.4–4.7) 4.0 (3.3–4.7) 
Median hemoglobin (range; g/dL) 12.6 (9.7–14.5) 12.8 (9.1–15.7) 
No. of patients with LDH > ULN 6 (43%) 15 (50%) 
 Median LDH (range; x ULN)a 1.2 (1.0–3.8) 1.3 (1.0–3.8) 
Primary tumor 
 Colorectal cancer 7 (47%) 17 (55%) 
 Pancreatic cancer 3 (20%) 4 (13%) 
 Biliary tract cancer .— 2 (7%) 
 Soft tissue sarcoma 1 (7%) 2 (7%) 
 Otherb 4 (27%) 6 (19%) 
Median number of metastatic sites (range) 3 (1–5) 3 (1–5) 
Sites of disease 
 Visceral 1 (7%) 8 (26%) 
 Nonvisceral 2 (13%) 3 (10%) 
 Both 12 (80%) 20 (65%) 
Prior treatment 
 Chemotherapy 15 (100%) 31 (100%) 
 Biological therapy 10 (67%) 22 (71%) 
 Radiotherapy 8 (53%) 16 (52%) 
 Investigational therapy 4 (27%) 9 (29%) 
Number of prior chemotherapy-containing regimens 
 Median 
 ≤2 5 (33%) 12 (39%) 
 4 or more 5 (33%) 10 (32%) 

Abbreviations: LDH, lactate dehydrogenase; RD, recommended dose.

aLDH values from patients with >ULN at baseline.

bAdenocarcinoma of unknown primary site, head and neck squamous cell carcinoma, melanoma, mesothelioma, prostate cancer, and salivary gland adenocarcinoma (n = 1 each).

A total of 97 PM01183 cycles were administered at 10 dose levels, of which 59 cycles (61%) were administered at the recommended dose, with a median of two cycles per patient; the median dose intensity was 2.3 mg flat dose/week and median relative dose intensity was 96.3% of the planned dose.

Dose-limiting toxicities and recommended dose

No grade 2 or higher toxicities were observed during escalation from the starting dose of 0.02 mg/m2 until dose level VII (1.3 mg/m2). Both patients treated at 2.6 mg/m2 (dose level VIII) had grade 1/2 nausea and/or vomiting, thus, standard antiemetic prophylaxis (ondansetron and dexamethasone, both intravenous, 20–30 minutes before PM01183 infusion) was made compulsory in all subsequent dose levels. DLTs were first observed in two of three patients treated at dose level IX (5.0 mg/m2) and consisted of grade 4 transaminase [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] increases (n = 2) and a combination of grade 4 neutropenia, grade 3 fatigue, and grade 2 diarrhea that resulted in patient withdrawal from the study (n = 1). According to the protocol definition, dose level IX (5.0 mg/m2) was defined as the MTD and dose escalation was terminated, consequently PM01183 dose was reduced by 20% to 4.0 mg/m2 and cohort scheme was then switched to a classical 3+3 design. None of the first six patients treated in this cohort had DLTs, though nonfebrile grade 4 neutropenia occurred in three patients. No relationship of plasma clearance and BSA was observed; therefore, nine additional patients were given a flat dose of 7.0 mg, approximately equivalent to 4.0 mg/m2 for most patients. One of 15 treated patients had a DLT (grade 4 thrombocytopenia), therefore confirming 4.0 mg/m2 or 7.0 mg flat dose as the recommended dose for PM01183 given as a 1-hour infusion q3wk.

Toxicity profile at the recommended dose

Of 31 patients, 15 (48%) were treated at the recommended dose and were evaluable for safety. All PM01183-related adverse events, at the recommended dose, were grade 1 or 2, the most common were nausea, fatigue, and vomiting despite mandatory antiemetic prophylaxis (Table 2). Hematologic abnormalities comprised anemia (93% of patients, grade 3: 27%, no grade 4 events), neutropenia (73%, grade 3/4: 53%), and thrombocytopenia (67%, no grade 3 events, grade 4: 7%; Table 2). Grade 4 neutropenia occurred in six patients (40%) at the recommended dose during cycle 1; the nadir (median count 0.2 × 109/L; range, 0.0–0.5 × 109/L) occurred on day +11 (range, 10–15 days), and the median duration was 3 days (range, 1–4 days). No febrile episodes complicated any neutropenia during this study. Grade 4 thrombocytopenia occurred in one patient during cycle 1; the nadir (9.2 × 109/l) was found on day +10 and returned to grade ≤2 within 3 days. There were only one cycle delay and two dose reductions at the recommended dose, all due to hematologic toxicity. Common biochemical abnormalities, irrespectively of their relationship, were mild alkaline phosphatase (67%) and ALT/AST increases (67% and 47%, respectively; Table 2). At the recommended dose, no biochemical abnormalities reached grade 4 severity, and grade 3 only occurred for ALT/AST increases (7% each) and creatinine increase in one patient (7%) with disease-related obstructive renal failure.

Table 2.

Drug-related adverse events (≥10% of patients) and laboratory abnormalities (hematologic and biochemical) at the recommended dose for phase II studies

PM01183
4.0 mg/m2 (or 7.0 mg FD)
Per patient (n = 15)Per cycle (cyc = 51)
NCI-CTCAE grade1–234Total1–234Total
Anorexia 2 (13%) — — 2 (13%) 3 (6%) — — 3 (6%) 
Diarrhea 3 (20%) — — 3 (20%) 4 (8%) — — 4 (8%) 
Fatigue 7 (47%) — — 7 (47%) 12 (24%) — — 12 (24%) 
Nausea 7 (47%) — — 7 (47%) 18 (35%) — — 18 (35%) 
Vomiting 7 (47%) — — 7 (47%) 10 (20%) — — 10 (20%) 
Hematologic laboratory abnormalities 
 Anemia 10 (67%) 4 (27%) — 14 (93%) 42 (82%) 4 (8%) — 46 (90%) 
 Neutropenia 3 (20%) 2 (13%) 6 (40%) 11 (73%) 7 (14%) 14 (27%) 7 (14%) 28 (55%) 
 Thrombocytopenia 9 (60%) — 1 (7%) 10 (67%) 25 (49%) 1 (2%) 1 (2%) 27 (53%) 
Biochemical laboratory abnormalities 
 ALT increased 9 (60%) 1 (7%) — 10 (67%) 18 (35%) 1 (2%) — 19 (37%) 
 AP increased 10 (67%) — — 10 (67%) 25 (49%) — — 25 (49%) 
 AST increased 6 (40%) 1 (7%) — 7 (47%) 10 (20%) 1 (2%) — 11 (22%) 
 CPK increased 2 (13%) — — 2 (13%) 6 (12%) — — 6 (12%) 
 Creatinine increased 2 (13%) 1 (7%) — 3 (20%) 3 (6%) 1 (2%) — 4 (8%) 
 Total bilirubin increased 3 (20%) — — 3 (20%) 8 (16%) — — 8 (16%) 
PM01183
4.0 mg/m2 (or 7.0 mg FD)
Per patient (n = 15)Per cycle (cyc = 51)
NCI-CTCAE grade1–234Total1–234Total
Anorexia 2 (13%) — — 2 (13%) 3 (6%) — — 3 (6%) 
Diarrhea 3 (20%) — — 3 (20%) 4 (8%) — — 4 (8%) 
Fatigue 7 (47%) — — 7 (47%) 12 (24%) — — 12 (24%) 
Nausea 7 (47%) — — 7 (47%) 18 (35%) — — 18 (35%) 
Vomiting 7 (47%) — — 7 (47%) 10 (20%) — — 10 (20%) 
Hematologic laboratory abnormalities 
 Anemia 10 (67%) 4 (27%) — 14 (93%) 42 (82%) 4 (8%) — 46 (90%) 
 Neutropenia 3 (20%) 2 (13%) 6 (40%) 11 (73%) 7 (14%) 14 (27%) 7 (14%) 28 (55%) 
 Thrombocytopenia 9 (60%) — 1 (7%) 10 (67%) 25 (49%) 1 (2%) 1 (2%) 27 (53%) 
Biochemical laboratory abnormalities 
 ALT increased 9 (60%) 1 (7%) — 10 (67%) 18 (35%) 1 (2%) — 19 (37%) 
 AP increased 10 (67%) — — 10 (67%) 25 (49%) — — 25 (49%) 
 AST increased 6 (40%) 1 (7%) — 7 (47%) 10 (20%) 1 (2%) — 11 (22%) 
 CPK increased 2 (13%) — — 2 (13%) 6 (12%) — — 6 (12%) 
 Creatinine increased 2 (13%) 1 (7%) — 3 (20%) 3 (6%) 1 (2%) — 4 (8%) 
 Total bilirubin increased 3 (20%) — — 3 (20%) 8 (16%) — — 8 (16%) 

NOTE: The number of patients/cycle with each adverse event is specified.

Hematologica and biochemical abnormalities are shown regardless of their relationship to treatment.

Abbreviations: AP, alkaline phosphatase; FD, flat dose.

Efficacy

Twenty-eight patients were evaluable for efficacy as per RECIST v.1.0; one confirmed partial response (PR) with tumor marker (CA19-9) normalization occurred in a patient with refractory pancreatic cancer treated at the recommended dose (Figs. 1 and 2). In addition, nine (29%) patients had disease stabilization as best response, which lasted for at least 4 months in five of them. Three of these five patients were treated at the recommended dose and all of them achieved longer progression-free survival (PFS) values with PM01183 when compared with their last prior therapy (Fig. 2). Overall, six patients showed evidence of some tumor shrinkage while on PM01183 treatment; five of them were treated at the recommended dose.

Figure 1.

Tumor shrinkage observed in one patient with pancreas adenocarcinoma who achieved PR with PM01183. Three lesions were observed in the liver at baseline (A). After three cycles of treatment with PM01183, two of these lesions disappeared and the third decreased from 29.8 mm to 16.5 mm (i.e., a tumor shrinkage of 45%; B). Changes in serum CA19-9 levels from baseline (BL) to cycle 10 (C).

Figure 1.

Tumor shrinkage observed in one patient with pancreas adenocarcinoma who achieved PR with PM01183. Three lesions were observed in the liver at baseline (A). After three cycles of treatment with PM01183, two of these lesions disappeared and the third decreased from 29.8 mm to 16.5 mm (i.e., a tumor shrinkage of 45%; B). Changes in serum CA19-9 levels from baseline (BL) to cycle 10 (C).

Close modal
Figure 2.

PFS values achieved before and after treatment with PM01183. Values are shown only for the four patients who were treated at the recommended dose and achieved PR (n = 1) or disease stabilization for ≥4 months (n = 3).

Figure 2.

PFS values achieved before and after treatment with PM01183. Values are shown only for the four patients who were treated at the recommended dose and achieved PR (n = 1) or disease stabilization for ≥4 months (n = 3).

Close modal

Pharmacokinetics

Pharmacokinetic data were available from 31 patients in cycle 1 and from seven patients treated at the recommended dose in cycle 2 (Table 3). PM01183 plasma concentrations increased linearly within the dose range explored, and clearance was independent of dose (P = 0.451). Pharmacokinetic variability was high; at the recommended dose, the CV of clearance was 57% in the first cycle, and somewhat lower (31%) in the second cycle, with a median intraindividual coefficient of variation of 30% (range, 5%–50%). None of the demographic and biochemical variables explored in this study had a significant impact on pharmacokinetic parameters; particularly, no significant relationship was found between BSA and clearance (P = 0.889), or between gender and clearance (P = 0.074). Urinary excretion of unaltered PM01183 was almost negligible regardless of dose; the mean percentage of unaltered drug recovered in urine at the recommended dose was 0.23%. To explore the effect of PM01183 on hematologic parameters, the survival fraction (ratio of nadir to baseline) was calculated (15) for the first cycle and used as the dependent variable for further analysis. There was a significant correlation of area under the concentration-time curve from time zero to infinity (AUC) with both log WBC survival fraction (r = −0.73, P = 0.0007) and log neutrophil survival fraction (r = −0.57, P = 0.016), which was stronger than the relationship with dose (Fig. 3).

Table 3.

Noncompartmental pharmacokinetic parameters of PM01183 1-hour three weekly schedule

Dose (mg/m2)nCmax (ng/mL)AUC (h*ng/mL)t½ (h)CL (l/h)Vss (l)
Cycle 1 
 0.02 1.5 (–) 2.7 (–) 3.9 (–) 15.2 (–) 68.9 (–) 
 0.04 4.4 (1.3) 7.5 (0.4) 5.1 (4.3) 10.6 (1.0) 64.3 (62.7) 
 0.08 4.1 (–) 5.6 (–) 1.8 (–) 26.6 (–) 53.8 (–) 
 0.16 7.3 (–) 24.5 (–) 14.6 (–) 11.9 (–) 161.9 (–) 
 0.32 23.1 (5.8) 125.9 (76.5) 53.9 (0.6) 6.9 (5.4) 340.3 (246.3) 
 0.64 33.4 (9.1) 125.6 (63.2) 98.2 (116.7) 11.8 (6.8) 754.9 (763.3) 
 1.3 70.4 (33.6) 286.0 (30.8) 48.2 (10.9) 7.9 (0.1) 363.4 (98.0) 
 2.6 147.0 (69.3) 502.1 (318.7) 39.1 (0.0) 12.2 (8.0) 336.2 (166.9) 
 4.0 or 7.0 mg FD 15 182.2 (85.9) 951.8 (850.0) 62.7 (45.5) 12.5 (7.1) 487.1 (201.9) 
 4.0 mg FD 233.2 (103.4) 777.4 (386.6) 50.9 (27.5) 11.9 (5.7) 402.5 (157.0) 
 7.0 mg FD 148.2 (54.6) 1068 (1064) 70.6 (54.6) 12.8 (8.2) 543.5 (216.7) 
 5.0 276.0 (141.4) 1127 (674.9) 37.7 (11.6) 9.3 (4.9) 314.9 (51.7) 
 7.0a 215.0 (–) 559.7 (–) 36.4 (–) 19.3 (–) 688.5 (–) 
Cycle 2 
 5.6 mg FDb 103.0 (–) 1057 (–) 123.4 (–) 5.3 (–) 799.7 (–) 
 7.0 mg FD 153.8 (60.4) 532.6 (194.4) 51.4 (9.1) 14.5 (4.4) 639.8 (193.5) 
Cycle 1 and 2 at 4.0 or 7 mg FD 
 Female 10 175.3 (50.7) 566.2 (320.3) 42.5 (21.3) 15.4 (6.3) 814.2 (245.6) 
 Male 11 172.9 (100.9) 1074.0 (937.3) 74.9 (45.1) 10.9 (5.9) 955.5 (413.2) 
Dose (mg/m2)nCmax (ng/mL)AUC (h*ng/mL)t½ (h)CL (l/h)Vss (l)
Cycle 1 
 0.02 1.5 (–) 2.7 (–) 3.9 (–) 15.2 (–) 68.9 (–) 
 0.04 4.4 (1.3) 7.5 (0.4) 5.1 (4.3) 10.6 (1.0) 64.3 (62.7) 
 0.08 4.1 (–) 5.6 (–) 1.8 (–) 26.6 (–) 53.8 (–) 
 0.16 7.3 (–) 24.5 (–) 14.6 (–) 11.9 (–) 161.9 (–) 
 0.32 23.1 (5.8) 125.9 (76.5) 53.9 (0.6) 6.9 (5.4) 340.3 (246.3) 
 0.64 33.4 (9.1) 125.6 (63.2) 98.2 (116.7) 11.8 (6.8) 754.9 (763.3) 
 1.3 70.4 (33.6) 286.0 (30.8) 48.2 (10.9) 7.9 (0.1) 363.4 (98.0) 
 2.6 147.0 (69.3) 502.1 (318.7) 39.1 (0.0) 12.2 (8.0) 336.2 (166.9) 
 4.0 or 7.0 mg FD 15 182.2 (85.9) 951.8 (850.0) 62.7 (45.5) 12.5 (7.1) 487.1 (201.9) 
 4.0 mg FD 233.2 (103.4) 777.4 (386.6) 50.9 (27.5) 11.9 (5.7) 402.5 (157.0) 
 7.0 mg FD 148.2 (54.6) 1068 (1064) 70.6 (54.6) 12.8 (8.2) 543.5 (216.7) 
 5.0 276.0 (141.4) 1127 (674.9) 37.7 (11.6) 9.3 (4.9) 314.9 (51.7) 
 7.0a 215.0 (–) 559.7 (–) 36.4 (–) 19.3 (–) 688.5 (–) 
Cycle 2 
 5.6 mg FDb 103.0 (–) 1057 (–) 123.4 (–) 5.3 (–) 799.7 (–) 
 7.0 mg FD 153.8 (60.4) 532.6 (194.4) 51.4 (9.1) 14.5 (4.4) 639.8 (193.5) 
Cycle 1 and 2 at 4.0 or 7 mg FD 
 Female 10 175.3 (50.7) 566.2 (320.3) 42.5 (21.3) 15.4 (6.3) 814.2 (245.6) 
 Male 11 172.9 (100.9) 1074.0 (937.3) 74.9 (45.1) 10.9 (5.9) 955.5 (413.2) 

NOTE: Values are expressed as mean (SD). Samples were collected in cycle 1 for all treated patients, and in cycle 2 for patients treated during cohort expansion at the recommended dose.

Abbreviations: AUC, area under the concentration-time curve from time zero to infinity; FD, flat dose; CL, total body clearance; Cmax, maximum plasma concentration; t½, terminal half-life; Vss, volume of distribution at steady state.

aAccidental overdose; see footnote of Table 2.

bDose was reduced after cycle 1 due to hematological toxicity.

Figure 3.

AUC (left) and dose (right) versus neutrophil ratio (top) and WBCs ratio (bottom) in cycle 1 at/over the recommended dose. The solid line represents the semi-log regression and the shadow area is the confidence region. The wide confidence regions for dose imply a weak relationship. RD, recommended dose.

Figure 3.

AUC (left) and dose (right) versus neutrophil ratio (top) and WBCs ratio (bottom) in cycle 1 at/over the recommended dose. The solid line represents the semi-log regression and the shadow area is the confidence region. The wide confidence regions for dose imply a weak relationship. RD, recommended dose.

Close modal

This first-in-human study met its goal of defining the recommended dose of PM01183 in an efficient manner. The accelerated titration design proved to be adequate and safe to allow a swift dose escalation more than 200 times, from the conservative starting dose of 0.02 mg/m2, derived from the MTD in the Sprague-Dawley rat. Similar to what has been described with other related compounds such as trabectedin, this starting dose, although safe, turned out to be poorly predictive of the human MTD. Should this trial have followed a more classical 3+3 Fibonacci design, it would have required significantly longer time to reach potentially therapeutic dosages. In contrast, almost half of participating patients in our study were treated at the recommended dose, thus maximizing the exposure to clinically relevant concentrations of the investigational treatment, while no unexpected toxicities occurred during escalation in this first-in-human study. This was in line with prior preclinical toxicology studies, which had shown myelosuppression and hepatotoxicity as primary PM01183 toxicities in mammals.

A flat dose of 7.0 mg (approximately equivalent to 4.0 mg/m2) q3wk was the highest dose level explored with less than one third of patients experiencing a DLT in cycle 1, and consequently was defined as the recommended dose for further phase II studies. Of note, one of the 15 patients treated at the recommended dose experienced a DLT (grade 4 thrombocytopenia). Nonetheless, grade 4 transient nonfebrile neutropenia occurring in 40% of these patients precluded any attempt to further escalate the recommended dose.

The regimen was generally well tolerated. Hematologic toxicity was predictable, manageable, and transient, whereas the schedule was suitable for most patients to receive their treatment on an ambulatory basis. All toxicities other than myelosuppression at the recommended dose were usually low grade and transient, the most common being nausea/vomiting and fatigue. Primary antiemetic prophylaxis with 5-HT3 antagonists plus a steroid was mandatory, although some patients might also need extended treatment in accordance with the American Society of Clinical Oncology guidelines (16).

Myelosuppression was the primary toxicity observed at the recommended dose or above it. Neutropenia correlated with dose, but particularly with AUC. The nadir occurred during the second week of the cycle in all cases, usually on day +11 (range, 10–15 days), and grade 4 lasted a median of 3 days (range, 1–5 days), thus allowing enough time to recovery without causing treatment delays in the majority of cases. Of note, no febrile neutropenia occurred, probably reflecting this relatively short duration and the relatively good condition of the patients participating in this study. Even if the eligibility criteria were standard for phase I, no patient treated at the recommended dose in this study was older than 75 years, had albumin level below 3.4 g/dL, or had an ECOG performance status score >1. At this time, it is speculative wherever PM01183-related myelosuppression is equally well tolerated in less selected patients; this remains to be tested prospectively. In addition, almost one third of patients treated at the recommended dose in this study had no neutropenia at all, which probably reflected the high interindividual pharmacokinetic variability. Myelosuppression does not seem to be cumulative, as most patients who experienced it did so during the first cycle, and no dose reductions or delays were required because of toxicity among patients receiving more than three cycles at the recommended dose or higher doses. The pharmacokinetic profile showed dose proportionality within the dose range tested and no drug accumulation between cycles was found, thus suggesting that administration every 3 weeks is safe and appropriate.

There was high interindividual variability in the clearance of PM01183, the source of which is yet unclear. PM01183 undergoes extensive microsomal metabolization in vitro; although the specific metabolic pathways and cytochromes involved remain to be fully elucidated. Theoretically, genetic differences in cytochromes or in membrane transporters at the protein expression level might contribute, at least partially, to explain the pharmacokinetic findings; ongoing pharmacogenomic studies will help to better characterize this observation. Renal excretion is a very minor route of elimination. Thus, changes in renal function are very unlikely to have an impact on the pharmacokinetic behavior of PM01183. Of note, the severity of the myelosuppression correlated with AUC measured during cycle 1; thus, understanding the causes of this variability might help to optimize patient exposure and thus reduce toxicity in the future. Finally, none of the explored demographic characteristics in this study, particularly BSA, had any significant impact on pharmacokinetics. Therefore, PM01183 flat dosing was successfully implemented at the recommended dose cohort expansion. Nonetheless, due to the limited number of patients treated in this study, none had a BSA outside the 1.47 to 2.48 m2 range. At the present, caution should be exercised when using the 7.0 mg flat dose recommended dose in populations different than those studied herein. In addition, further analysis to check any potential difference in clearance between males and females is warranted (see Table 3).

Antitumor efficacy was confirmed, despite extensive prior treatment. Most patients included in this study had colorectal tumors and had received three or more previous lines of chemotherapy for advanced disease and therefore were very unlikely to respond to any therapy at that point. Nevertheless, evidence of antitumor activity in this study was found in a refractory pancreatic cancer patient who had a confirmed PR with tumor marker normalization, as well as in three patients (two with soft-tissue synovial sarcomas and one with a malignant melanoma) who had prolonged disease stabilizations with some radiological evidence of tumor shrinkage. Comparison of the PFS achieved on PM01183 with that on the immediately prior treatment line suggests that the stable disease might be due to PM01183 treatment (as opposed to an indolent natural history, see Fig. 2).

In conclusion, PM01183 administered as a 1-hour infusion q3wk to adult patients with refractory solid tumors was well tolerated. It is active at its recommended dose of 7.0 mg flat dose, and caused primarily severe but reversible, limited, and predictable neutropenia in this study. This schedule is now being evaluated in several phase II clinical trials; the results, when available, will provide valuable additional information on safety, feasibility, and pharmacokinetic behavior in a much wider patient population, as well as confirm its preliminary antitumor activity in specific disease settings.

S.P. Kang is employed by Merck & Co Inc. A. S.-M. Pita is employed by and has ownership interest (including patents) in PharmaMar. M. Siguero has ownership interest (including patents) in PharmaMar. S. Szyldergemajn is employed by PharmaMar. M.J. Ratain has received a commercial research grant from PharmaMar. No potential conflicts of interest were disclosed by the other authors.

Conception and design: M.E. Elez, J. Tabernero, C. Kahatt, C. Fernandez-Teruel, M. Siguero, S. Szyldergemajn, M.J. Ratain

Development of methodology: M.E. Elez, J. Tabernero

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.E. Elez, J. Tabernero, D. Geary, T. Macarulla, S.P. Kang, C. Fernandez-Teruel, M.J. Ratain

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.E. Elez, J. Tabernero, A.S.-M. Pita, C. Fernandez-Teruel, M. Siguero, M. Cullell-Young, S. Szyldergemajn, M.J. Ratain

Writing, review, and/or revision of the manuscript: M.E. Elez, J. Tabernero, S.P. Kang, C. Kahatt, A.S.-M. Pita, C. Fernandez-Teruel, M. Siguero, M. Cullell-Young, S. Szyldergemajn, M.J. Ratain

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): D. Geary, C. Fernandez-Teruel, M. Siguero, M.J. Ratain

Study supervision: J. Tabernero, D. Geary, S. Szyldergemajn, M.J. Ratain

This work was supported by Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Rinehart
KL
,
Holt
TG
,
Fregeau
NL
,
Keifer
PA
,
Wilson
GR
,
Perun
TJ
 Jr
, et al
Bioactive compounds from aquatic and terrestrial sources
.
J Nat Prod
1990
;
53
:
771
92
.
2.
Manzanares
I
,
Cuevas
C
,
Garcia-Nieto
R
,
Marco
E
,
Gago
F
. 
Advances in the chemistry and pharmacology of ecteinascidins, a promising new class of anti-cancer agents
.
Curr Med Chem Anticancer Agents
2001
;
1
:
257
76
.
3.
Leal
JF
,
Martinez-Diez
M
,
Garcia-Hernandez
V
,
Moneo
V
,
Domingo
A
,
Bueren-Calabuig
JA
, et al
PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity
.
Br J Pharmacol
2010
;
161
:
1099
110
.
4.
Guillen
MJ
,
Cataluña
O
,
Palomares
M
,
Lopez
R
,
Cuevas
C
,
Aviles
P
. 
In vivo combination studies of PM01183 with alkylating, antimetabolites, DNA-topoisomerase inhibitors and tubulin binding agents
[abstract]
. In:
Proceedings of the AACR 102nd Annual Meeting; 2011 April 2–6
;
Orlando FL. Philadelphia, PA
:
AACR
; 
2011
.
Abstract nr 3538
.
5.
Soares
DG
,
Machado
MS
,
Rocca
CJ
,
Poindessous
V
,
Ouaret
D
,
Sarasin
A
, et al
Trabectedin and its C subunit modified analogue PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant cells
.
Mol Cancer Ther
2011
;
10
:
1481
9
.
6.
Aviles
P
,
Galmarini
C
,
Cuevas
C
,
Guillen
MJ
,
Frapolli
R
,
Uboldi
S
, et al
Mechanism of action and antitumor activity of PM01183. 100th Annual Meeting of the American Association for Cancer Research (AACR)
; 
2009
;
Denver, Colorado
;
abstract 2679
.
7.
Soares
DG
,
Larsen
AK
,
Escargueil
AE
. 
The DNA damage response to monofunctional anticancer DNA binders
.
Drug Discov Today
2012
;
9
:
59
67
.
8.
U.S. Food and Drug Administration Guidance for industry
. 
Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers
. 
2005
. http://www.fda.gov/Drugs/GuidancecomplianceRegulatoryInformation/Guidances/default.htm.
9.
The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation Unit
.
Note for guidance on the pre-clinical evaluation of anticancer medicinal products
. 
1998
. http://www.iss.it/binary/scf1/cont/CPMP_SWP_997_96.pdf.
10.
Guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals
. 
2008
. http://www.fda.gov/RegulatoryInformation/Guidances/ucm129520.htm.
11.
Undevia
SD
,
Vogelzang
NJ
,
Mauer
AM
,
Janisch
L
,
Mani
S
,
Ratain
MJ
. 
Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors
.
Invest New Drugs
2004
;
22
:
449
58
.
12.
National Cancer Institute (2006) Common Terminology Criteria for Adverse Events v3.0 (CTCAE)
. http://www.eortc.be/services/doc/ctc/ctcaev3.pdf.
13.
Therasse
P
,
Arbuck
SG
,
Eisenhauer
EA
,
Wanders
J
,
Kaplan
RS
,
Rubinstein
L
, et al
New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada
.
J Natl Cancer Inst
2000
;
92
:
205
16
.
14.
Wickham
H
. 
ggplot2: Elegant Graphics for Data Analysis
.
New York
:
Springer
; 
2009
.
15.
Ratain
MJ
,
Schilsky
RL
,
Conley
BA
,
Egorin
MJ
. 
Pharmacodynamics in cancer therapy
.
J Clin Oncol
1990
;
8
:
1739
53
.
16.
Kris
MG
,
Hesketh
PJ
,
Somerfield
MR
,
Feyer
P
,
Clark-Snow
R
,
Koeller
JM
, et al
American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006
.
J Clin Oncol
2006
;
24
:
2932
47
.