Invest New Drugs DOI 10.1007/s10637-014-0072-y

PHASE I STUDIES

Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors Ramón Salazar & Antonio Calles & Marta Gil & Ignacio Durán & Margarita García & Manuel Hidalgo & Cinthya Coronado & Vicente Alfaro & Mariano Siguero & Carlos Fernández-Teruel & Raquel Prados & Emiliano Calvo

Received: 18 November 2013 / Accepted: 5 February 2014 # Springer Science+Business Media New York 2014

Summary This phase I trial determined the recommended dose for phase II trials (RD) of carboplatin 1-h intravenous (i.v.) infusion followed by PM00104 1-h i.v. infusion on Day 1 every 3 weeks (q3wk) in adult patients with advanced solid tumors. A toxicity-guided, dose-escalation design was used. Patients were stratified and divided into heavily (n=6) or mildly pretreated (n=14) groups. Transient grade 4 thrombocytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m2 was the RD in both groups. At this RD, the carboplatin AUC was equal to ~60 % the target AUC used in other combinations, and the PM00104 dose intensity was 56–67 % of the value achieved at the RD for single-agent PM00104 given as 1-h infusion q3wk. Most treatment-related adverse events were grade 1/2. They mainly consisted of gastrointestinal and general symptoms, such as fatigue, anorexia, mucosal inflammation or nausea. Transient neutropenia (50 % of patients) and thrombocytopenia (33– 38 %) were the most common severe hematological abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. Partial response was found in one patient with triple negative breast cancer pretreated with paclitaxel/ bevacizumab. Three patients with colorectal cancer, head R. Salazar : M. Gil : M. García Instituto Catalán de Oncología, L’Hospitalet de Llobregat, Barcelona, Spain A. Calles : I. Durán : M. Hidalgo : E. Calvo (*) START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte Sanchinarro, C/Oña 10, 28050 Madrid, Spain e-mail: [email protected] C. Coronado : V. Alfaro : M. Siguero : C. Fernández-Teruel : R. Prados PharmaMar, Clinical R&D, Colmenar Viejo, Madrid, Spain

and neck cancer, and tumor of unknown origin had disease stabilization for ≥3 months. In conclusion, no optimal dose was reached due to overlapping myelosuppression despite stratification according to prior treatment. Therefore, this carboplatin plus PM00104 combination was not selected for further clinical research. Keywords Phase I . PM00104 . Carboplatin . Antitumor . Cytotoxic . Dose-limiting toxicities

Introduction PM00104 (Zalypsis®) is a synthetic cytotoxic alkaloid structurally related to marine compounds jorumycins and renieramycins [1–3]. The antitumor effects of PM00104 are exerted through covalent modification of guanines in the DNA minor groove. This results in double-strand DNA breaks, S-phase arrest and apoptosis in cancer cells [4–7]. Preclinical studies showed promising antitumor activity and acceptable pharmacokinetic (PK) and toxicity profiles [4, 7–15]. Based on these findings, several phase I clinical trials have evaluated different single-agent schedules [16–18]. One of these trials evaluated a 1-h intravenous (i.v.) infusion every 3 weeks (q3wk) schedule. The most common PM00104-related adverse events (AEs) were mild-moderate nausea and fatigue. The most frequent severe hematological abnormalities were transient neutropenia and leukopenia. No dose-limiting toxicities (DLTs) occurred at the recommended dose for phase II trials (RD) of 3.0 mg/m2 [16]. Overall, relevant tumor shrinkage was found in one patient with urothelial carcinoma [16] and prolonged disease stabilizations in several patients with difficult-to-treat diseases [16–18]. Phase II clinical trials are assessing PM00104 in patients with advanced endometrial/cervical cancer [19], advanced Ewing

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family of tumors [20], multiple myeloma, and advanced urothelial cancer (www.clinicaltrials.gov/). PM00104 combined with cisplatin showed significant in vivo synergism against human gastric and bladder xenografts [21]. This combination was not associated with unexpected toxicities. Another platinum compound, carboplatin, is easy to administer and has shown activity against the same tumor types than PM00104. No preclinical data are available on the effects and toxicities of PM00104 combined with carboplatin, but the results obtained with the PM00104/ cisplatin combination may be extrapolated. Hence, a phase I clinical trial was designed to identify the RD of carboplatin combined with PM00104 in patients with advanced malignant solid tumors for which no conventional therapies were available. The PK profile and preliminary antitumor activity of this combination were also evaluated.

monoclonal antibodies or bicalutamide). Radiotherapy was not allowed within 4 weeks before PM00104 administration (within 8 weeks for extensive radiotherapy). Patients were excluded if they had any of the following: progressive or corticosteroid-requiring brain or leptomeningeal metastases; significant non-neoplastic liver or renal disease; increased cardiac risk (unstable angina, myocardial infarction within the last 6 months; significant valvular heart disease; congestive heart failure; symptomatic arrhythmia; abnormal electrocardiogram; uncontrolled arterial hypertension; previous mediastinal radiotherapy, or previous treatment with doxorubicin or epirubicin at cumulative doses >400 mg/m2 or >900 mg/m2, respectively); or other relevant clinical conditions (active infection or immunodeficiency). Patients were also excluded if they were pregnant or breast-feeding women, or if they were not using appropriate contraceptive measures. The eligibility criteria stated no limit to the number of prior chemotherapy lines.

Materials and methods Study treatment This study was conducted at two medical centers in Spain (Instituto Catalán de Oncología, L’Hospitalet de Llobregat, Barcelona, and START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte Sanchinarro, Madrid) in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, and was approved by the respective independent ethics committees and by the Competent National Authorities. Written informed consent was obtained from all enrolled patients. Selection of patients Eligible patients were ≥18 years old with histologically confirmed cancer not amenable to conventional treatment; with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2; with recovery from toxicities of previous treatments (except for alopecia or grade 2 lines of chemotherapy; > 6 cycles of an alkylating agent or carboplatin in combination therapy; therapy with mitomycin-C or any nitrosoureas; high-dose therapy; or irradiation to more than 25 % of bone marrow-bearing areas. DLTs were defined as follows: grade 4 neutropenia lasting >7 days; febrile neutropenia or neutropenic infection; grade 4

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thrombocytopenia; grade 3/4 ALT or AST increase lasting ≥7 days; any other treatment-related grade 3/4 nonhematological toxicity except for nausea, vomiting and/or diarrhea (unless the patient received optimal antiemetic or antidiarrheic treatment), hypersensitivity reactions or nonclinically relevant biochemical abnormalities; dosing delay >2 weeks due to persistent toxicity; troponin I increase ≥0.1 ng/ml with evidence of cardiac damage by echocardiography or electrocardiogram (ECG); and LVEF decrease >20 % from baseline. Each cohort initially consisted of three patients. If one of these patients had a DLT, up to three more patients were treated at that dose level. The maximal tolerated dose (MTD) was the highest dose level at which ≥2 patients in a cohort of 3–6 patients had DLTs. The RD was the highest dose level at which 2 6 (100.0 %)

%) %) %) %)b

(carboplatin) and 0.56 mg/m2/week (PM00104) in heavily pretreated patients. In mildly pretreated patients, these parameters were 3.5 cycles per patient (range, 1–8), and 57 mg/week (carboplatin) and 0.67 mg/m2/week (PM00104), respectively. Overall, 4 cycles were delayed in three heavily pretreated patients at the RD. Three delays were due to treatment-related neutropenia and one was due to Port-ACath replacement. One PM00104 dose was reduced in one patient due to treatment-related grade 4 neutropenia and thrombocytopenia. In the mildly pretreated group, eight dosing delays occurred in three patients at the RD. Two patients had one delay each due to treatment-related neutropenia alone or concomitant with thrombocytopenia. In addition, a 60-year-old male with unknown primary origin carcinoma had six delays due to treatment-related neutropenia alone (n=5) or concomitant with grade 2 ejection fraction decrease (n=1). In this last case, the patient’s LVEF decreased from 58 % at baseline (lower limit of normality=55 %) to 45 % in Cycle 3, and then remained stable (47 % in Cycle 5, 48 % in Cycle 7, and 44 % in Cycle 8).

Toxicity profile at the recommended dose

d

13 (92.9 %) 7 (50.0 %) 8 (57.1 %) 2 0–3 12 (85.8 %) 1 (7.1 %)e

Data shown are n (%) of patients a Head and neck cancer, NSCLC and unknown origin (n=1 each) b Bladder cancer, cholangiocarcinoma, cystic adenoid carcinoma, esophagus squamous carcinoma, head and neck cancer, malignant melanoma, STS, and unknown origin (n=1 each) c Median number of lesions per patients was 2 (range, 1–3) in the two stratification groups d One patient with cystic adenoid carcinoma had not received any systemic anticancer therapy (no standard chemotherapy for this type of tumor exists) e One patient had received two lines of systemic anticancer therapy in the advanced setting and one line in the adjuvant setting; the two advanced lines did not include alkylating agents or platinum compounds ECOG Eastern Cooperative Oncology Group; NSCLC non-small cell lung cancer; STS soft tissue sarcoma

Drug exposure at the recommended dose At the RD, the median of cycles administered per patient was 4 (range, 1–6), and the median dose intensity was 58 mg/week

Most treatment-related AEs at the RD were mild or moderate. The most common were gastrointestinal and general symptoms (Table 3). In heavily pretreated patients, three AEs reached grade 3 in the same patient: nausea and vomiting in Cycle 1, and diarrhea in Cycle 2. The grade 3 nausea and vomiting were not considered DLTs because they resolved within 3 days after administration of standard optimum antiemetic treatment. Only one mildly pretreated patient had a grade 3 AE: one episode of hypersensitivity, which was related to carboplatin. Neutropenia was the most frequent severe hematological abnormality in both stratification groups, irrespective of grade or relationship with treatment. Grade ≥3 neutropenia started at a median of 15 days (range, 14–21 days) after dosing and recovered to grade ≤2 at a median of 7 days (range, 4–7 days) in heavily pretreated patients. In mildly pretreated patients, it started at a median of 19 days (range, 12–21 days) after dosing and recovered to grade ≤2 at a median of 7 days (range, 2– 9 days). Episodes of transient neutropenia were the most common reason for treatment-related dose delays. No cases of febrile neutropenia were reported. Grade ≥3 thrombocytopenia (the only DLT reported in this trial) started at a median of 15 days (range, 14–15 days) after dosing and recovered to grade ≤2 at a median of 4 days (range, 2–6 days) in heavily pretreated patients. It started at a median of 13 days (range, 8– 13 days) after dosing and recovered to grade ≤2 at a median of 7 days (range, 5–11 days) in mildly pretreated patients.

Invest New Drugs Table 2 Dose escalation scheme, distribution of patients, number of cycles and dose-limiting toxicities in cycle 1 Dose level

Dose Carboplatin (AUC)

No. of cycles

Median (range) of cycles

Patients

Patients with DLTs in Cycle 1

Description of DLTs

2.0

23

4 (1–6)

6

1

Grade 4 thrombocytopenia

2.0 2.0

31 28 59

3.5 (1–8) 3.5 (1–11) 3.5 (1–11)

8 6 14

1 2 3

Grade 4 thrombocytopenia Grade 4 thrombocytopenia (n=2)

PM00104 (mg/m2)

Heavily pretreated patients I (RD) 3 Mildly pretreated patients I (RD) 3 II (MTD) 4 Total

Carboplatin plus PM00104 1-h i.v. infusions were administered as a Day 1 q3wk schedule AUC area under the curve; DLT dose-limiting toxicity; i.v. intravenous; MTD maximal tolerated dose; q3wk every 3 weeks; RD recommended dose for phase II studies

Table 3 Treatment-related adverse events and laboratory abnormalities (≥20 % of patients) at the recommended dose for phase II studies RD = Carboplatin AUC3/PM00104 2.0 mg/m2 NCI-CTCAE grade

Adverse events Anorexia Constipation Diarrhea Edema Fatigue Hypersensitivitya Mucosal inflammation Nausea Vomiting Hematological abnormalitiesb Anemia Neutropenia Thrombocytopenia Biochemical abnormalitiesb Amylase increased ALT increased AP increased AST increased Creatinine increased Total bilirubin increased a

Heavily pretreated patients (n=6)

Mildly pretreated patients (n=8)

1–2

1–2

3–4

3–4

n

%

n

%

n

%

n

%

3 2 – 2 5

50 33 – 33 83

– – – – –

– – – – –

3 1 2 – 7

38 13 25 – 88

– – – – –

– – – – –

1 2 4 1

17 33 67 17

– – 1 1

– – 17 17

1 3 3 2

13 38 38 25

1 – – –

13 – – –

6 2 3

100 33 50

– 3 2

– 50 33

7 2 5

88 25 62

1 4 3

12 50 38

2 – 1 1 – –

40c – 17 17 – –

– – – – – –

– – – – – –

– 2 4 3 2 2

– 25 50 38 25 25

– 2 – 1 – 1

– 25 – 12 – 12

Related only to carboplatin Hematological and biochemical laboratory abnormalities are shown regardless of their relationship to treatment c Data available for five patients ALT alanine aminotransferase; AP alkaline phosphatase; AST aspartate aminotransferase; AUC area under the curve; NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events; RD recommended dose for phase II studies b

Invest New Drugs Table 4 Non-compartmental pharmacokinetic parameters of carboplatin plus PM00104 Day 1 q3wk schedule PM01004 Dose 2 mg/m2 Free carboplatin

na 18

Cmax (μg/l) 29.55±6.43

AUC (μg⋅h/l) 80.28±28.61

CL (l/h) 48.0±16.9

Vss (l) 657±249

Terminal t½ (h) 19.3±8.4

AUC3

13

Cmax (mg/ml) 0.015±0.005

AUC (mg⋅min/l) 2.47±0.49

CL (l/h) 8.5±2.2

Vss (l) 28.4±7.6

Terminal t½ (h) 4.1±1.1

AUC4

6

0.024±0.005

3.56±0.83

7.8±1.4

21.3±5.4

3.5±0.9

Results shown are mean ± standard deviation Data obtained during the first cycle a Nineteen of 20 treated patients had PK sampling assessable for non-compartmental pharmacokinetics analysis. Additionally, the PM00104 PK profile of one patient was withdrawn due to an unexpected PK shape AUC area under the curve; CL clearance; Cmax maximal plasma concentration; PK pharmacokinetic; t1/2 half-life; Vss volume of distribution in steady state

No severe biochemical abnormalities were reported in heavily pretreated patients. Those found in mildly pretreated patients had no effects on study treatment. No toxic deaths occurred during the study. One heavily pretreated patient died due to streptococcal sepsis unrelated to treatment. Pharmacokinetics Relevant PK data are shown in Table 4. Prior therapy did not alter the PK profile of PM00104 or free carboplatin. The results were very similar in mildly and heavily pretreated patients (data not shown). Antitumor activity No objective response or disease stabilization for ≥3 months occurred in heavily pretreated patients. Three patients achieved stable disease for