MBP-426, a novel liposome-encapsulated oxaliplatin, in combination with 5-FU/leucovorin (LV) – Phase I results of a Phase I/II study in gastro-esophageal adenocarcinoma, with pharmacokinetics
Abstract #C36

N. N. Senzer1, K. Matsuno2, N. Yamagata2, T. Fujisawa2, E. Wasserman3, W. Sutherland4, S. Sharma5, A. Phan6
1: MCCRC, Dallas, TX; 2: Mebiopharm Co., Ltd., Tokyo, Japan; 3: AAIPharma, San Antonio, TX; 4: AAIPharma, Le Kremlin Bicêtre, France; 5: Huntsman Cancer Institute, Salt Lake City, UT; 6: M.D.Anderson Cancer Center, Houston, TX

Pharmacokinetic assessments
Clinical PK studies were performed for all patients treated in the phase Ib part.
Sampling schedule• Cycle 1: Baseline, end of infusion, then 0.5, 1, 2, 4, 8, 24, 48, and 72 hr after the end of
the infusion• Cycle 2: Baseline, end of infusion, then 0.5, 1, 2, 4, and 8 hr after the end of theinfusion

At dose level 226 mg/m2, during the first cycle, an episode of back pain (probably
related to the liposomal formulation) and grade 3 nausea-vomiting were the dose
limiting toxicities. However, the observation of more cycles showed that the mostfrequent severe toxicity was thrombocytopenia, with three out of four patients
experiencing grade 3-4 thrombocytopenia. The grade 4 events were documented
during the second cycle. No febrile neutropenia was observed.

MBP-426 is a liposomal drug product inwhich the drug substance oxaliplatin is
encapsulated within a liposome, and humantransferrin is attached to the liposome
surface. The lipid is organized as a bilayer
with an acceptable range of the principal
peak between 50-200 nm.
Thetransferrin-conjugatedliposomal
oxaliplatin
formulation
MBP-426
wasdeveloped to improve the safety andefficacy
ofoxaliplatinthrough
theprolongation of drug circulation time inplasma and by targeting transferrin
receptors on tumor cells.

5-FU/LV (de Gramont regimen).
• MBP-426 is administered every 21 days as an IV infusion with a starting dose of 226 mg/m2.
• MBP-426 is provided in 30 mL vials containing 24 mg. No dilution is required. MBP-426
infusion rate will start at 75 mL/hr for 15 minutes, will increase to 100 mL/hr for the next 15
minutes, and then increase to a maximum of 150 mL/hr for the remainder of drug
administration.
• Following MBP-426 administration, leucovorin (400 mg/m2) is administered with an IV bolusof 400 mg/m2 fluorouracil, followed by 2400 mg/m2 fluorouracil continuous IV (CIV) infusion
over 46 hours.

Efficacy assessment
Efficacy was assessed according to RECIST at the end of every 2 cycles. Confirmatory
scans were obtained > 4 weeks after documentation of an objective response.

A previous phase I clinical study (Sankhala et al, 2009) reported the exploration of
MBP-426 as a single agent in solid tumors. MBP-426 was administered by 2-hr IV
infusion q3w. This dose-finding study explored doses from 6 mg/m2 to 400 mg/m2 in 39
patients. Thrombocytopenia was the dose limiting toxicity, with DLTs reported in one
patient treated at 226 mg/m2 (grade 4 thrombocytopenia), and 2 patients at 400 mg/m2(grade 4 thrombocytopenia, and grade 2 thrombocytopenia lasting >14 days);
226 mg/m2 was the recommended dose for phase II studies.

PATIENT CHARACTERISTICS
Between May and September 2009, a total of 10 patients were included and treated in
the phase I part of the study. A total of 14 cycles were administered at the starting
dose of 226 mg/m2, and 16 cycles were administered at the lower dose of 170 mg/m2.
Most of the treated patients had received some prior platinum-based treatment, and 4
patients were oxaliplatin resistant.

The current phase I-II study was designed to establish the RD of MPB-426 incombination with 5-FU/LV (de Gramont schedule) and assess the efficacy of thiscombination in second-line patients with gastro-esophageal (GE) adenocarcinoma.
Here we report the phase I data.

Study Objectives
Primary Objective
Phase Ib: To determine the RD of MBP-426 in combination with 5-FU/LV (de Gramontschedule) administered every 21 days.
Phase II: To measure the objective tumor response rate (RECIST) in patients withsecond line metastatic gastric, gastro-esophageal junction, or esophageal
adenocarcinoma.

Secondary Objectives
Phase Ib:• To characterize the safety profile• To undertake a preliminary exploration of anti-tumor activity of• To determine the plasma and urine pharmacokinetics of MBP-426 in combination
with 5-FU/LV
Phase II:• To characterize the safety profile of the combination therapy

Dose escalation was to follow a standard
3+3 paradigm. The MTD is defined as thedose level below that which produces DLTs
in at least one-third of evaluable patientsduring Cycle 1.

-1 Dose de-escalation
MBP-426 STARTING DOSE
Intermediate dose
+1 Dose Escalation

Dose Modification and Re-Treatment
On the planned day of treatment, chemotherapy may only be administered if:•the neutrophil count is >1.5 x109/L•the platelet count is >100 x109/L•other chemotherapy-related toxicity < grade 1 (except for alopecia and acne-like rash)
If dosing is delayed for longer than 2 weeks, the patient will be removed from study.

Eligibility Criteria
Inclusion criteria

Exclusion Criteria

Phase Ib:
• Advanced or metastatic solid tumor malignancy that is refractory to standard therapy or forwhich conventional therapy is not reliably effective, or no effective therapy is available.
• Measurable disease as defined by RECIST.
• Age 18 years or older.
• ECOG PS of 0, 1, or 2.
• Adequate organ and system function defined by the following parameters:• Bone marrow: (ANC of ≥1500/mm3, platelet count ≥100,000/mm3, and HB ≥9 g/dL;• Coagulation: PT <1.3 x ULN, PTT >LLN, <1.1 x ULN;
• Renal: Serum creatinine of ≤1.5 x ULN or calculated creatinine
clearance ≥60 mL/min/1.73m2;• Hepatic: Total bilirubin ≤1.5 mg/dL, ALT and AST ≤2.5 x ULN (or 5 x ULN in the case of livermetastases), and alkaline phosphatase ≤2.5 x ULN (or 5 x ULN in the case of livermetastases)• Recovered to ≤Grade 1 from all acute toxicities• If of childbearing potential, agree to use an effective method of contraception.
•Provide written informed consent.

Phase Ib and II:• Radiotherapy or major surgery within 14 days prior to study enrollment.
• Anticancer therapy (chemotherapy, radiotherapy, hormonal therapy, immunotherapy, orinvestigational agents) within 30 days of enrollment (6 weeks for mitomycin C).
•Known or clinical evidence of central nervous system (CNS) metastases.
• Receiving high-dose steroids (more than a dexamethasone-equivalent dose of 4 mg perday).
• Current active infections or significant intercurrent illnesses.
• Documented or known hematologic malignancy and/or bleeding disorder.
• Peripheral neuropathy ≥ grade 2 (NCI-CTCAE, Version 3.0).
• Any requirement(s) for therapeutic anticoagulation (low dose deep vein thrombosis[DVT] or line prophylaxis is allowed).
• History of allergy to any of the treatment components (oxaliplatin, 5-FU, folinic acid,liposome, ferritin).

Phase II:
• Inoperable, histologically, or cytologically confirmed, locally advanced or metastatic gastric,
gastro-esophageal junction, or esophageal adenocarcinoma that has recurred or progressedfollowing 1 prior chemotherapy.
• Measurable disease as defined by RECIST.
AACR-NCI-EORTC “Molecular Targets and Cancer Therapeutics”: November 15-19, 2009, Boston MA, USA

Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4

Neutropenia

122

2

Thrombocytopenia-311N
10 / 10Anemia

3-

312

Dose Level 226 mg/m

6Diarrhea

3-

3-

2

Dose Level 170 mg/m

4Nausea-vomiting

31

3-Age, median (range)

60.5 (44-67)

Back pain-1--Fatigue

2-

2-

5/5
2/8/0Skin

CRC

5Pancreas

2Cervix

1HyN

1Bladder1

N metastatic sites, median2

Number of previous systemic lines,
median (range)

4 (2-10)Previous platinum-based treatment

9

Oxaliplatin resistant

4DLTs AND DETERMINATION OF THE MAXIMUM TOLERATED DOSE
Two dose levels were explored: 226 and 176 mg/m2. Two patients experienced DLT atthe starting dose level of 226 mg/m2 MBP-426. Enrollment continued at the nextlowest dose level (170 mg/m2); 6 patients were included and treated at this dose level,with no DLTs observed. Thus 170 mg/m2 is the recommended dose to be used with
FU/Leucovorin (de Gramont regimen), and is currently being explored in the phase II
part of the study.
Table 2. Incidence of DLTPatient

170 mg/m
6 Patients
16 Cycles-Primary tumor

Dose Limiting Toxicity (defined during Cycle 1)
Grade 4 neutropenia persisting for at least 5 days;
Grade 3 to 4 neutropenia associated with fever ≥38.5°C, IV antibiotics, or hospitalization forinfection;
Grade 4 thrombocytopenia persisting for at least 5 days or Grade 3 thrombocytopenia withbleeding and need for platelet transfusions;
Grade ≥ 3 diarrhea persisting for more than 24 hours in spite of optimal medical management
Any other Grade ≥ 3 non-hematological toxicity considered related and clinical relevant

226 mg/m
4 Patients
14 Cycles-

PS 0 / 1 / 2

170 mg/m
2
226 mg/m
263 mg/m2
301 mg/m2

2-

Sex M / F22-

N patients included / treated

Dose escalation
In the Phase Ib portion of this study, the first cohort of patients were to receive MBP-426 at adose of 226 mg/m2. Subsequent patients were to be treated at doses in accordance with thetable below.

Table 3. Treatment-Related Adverse Events (CTCAE v3) – Maximum grade per patient

Febrile Neutropenia

Table 1. Patient characteristics

Prophylactic medication
Patients are premedicated 15 minutes prior to MBP-426 infusion as follows: 10 mg
dexamethasone (IV), 8 mg Zofran, and 25 mg Benadryl.

At the recommended dose level of 170 mg/m no grade 3-4 non hematological adverse
events were observed, while one out of 6 patients had grade 3 thrombocytopenia.

MBP-426
Dose Level

SafetyMBP-426 has shown efficacy in non-clinical in vivo studies using the following humanxenograft tumor models: MX-1 (breast), HCT-116 (colon), HT-29 (colon), MKN45(gastric), COLO 205 (colon), NCI-N87 (gastric), and PANC-1 (pancreas).

2TumorCyclesDLT

Reason for Discontinuation

Dose level 226 mg/m2
#01

CRC

4NO

G3 Erythema Multiforme at Cycle 4#02

Bladder

1

G3 NauseaVomiting

GI toxicity-Anorexia

12

Abdominal Pain-2-

11--Bilirubin (↑)-1--Creatinine (↑)

1-sampling schedule is taken into account.

•At a dose of 170 mg/m², MBP-426 results in Cmax and AUC exposure approximately
10 times higher than oxaliplatin 130 mg/m² (Graham et al, 2000).

•The reported half-lives do not provide an accurate estimate, given that sampling did

not cover a sufficiently long period, and are provide for information only.
Table 5. Total plasma platinum pharmacokinetic parameters

DL (mg/m2)
Cycle
N patientsCmax(µg/mL)T½(h)AUC0-12h(µg.h/mL)
AUC0-last(µg.h/mL)
AUC0-∞(µg.h/mL)
Clearance(mL/h/m²)
Vz(L/m²)

1 (AST)170
1651.27
1729.6
30
441.7
20
1674
49
2212
3676.84
36
3.29
32

Mean
CV
Mean
CV
Mean
CV
Mean
CV
Mean
CV
Mean
CV
Mean
CV-

100

90800
Central point is mean
Box is standard error
Whisker is standard deviation
Outllying points are outliers

700

80

70

60

DiseaseCycles

MBP-426
Cumulative Dose2(mg/m )Peripheral Neurotoxicity
Grade

#01

CRC

4900

G1 *#03

Pancreas

51070

-

#04

CRC

4900-

#05

Cervix4680-

6005004005030030200170

226

Dose Level (mg/m²)

Table 4. Peripheral neurotoxicity in patients with significant cumulative dosePatient

226
2280.24
2625.854710.7
21711
2130767273.4672
2.74
14Cycle 1Cycle 2

40

No treatment-emergent peripheral neurotoxicity was reported, despite significant
cumulative doses of oxaliplatin in 4 patients (see below); grade 1 peripheral
neurotoxicity was reported by one patient who exhibited this at baseline.

2261
372.361545.566577.4
20211455
3720
5860.76
58
3.99
23900

110--

1702648.61
2124.3
54
402.3
22453
2617074299.58
423.4919

Figure 1. Total plasma platinum Cmax and AUC0-12h in cycles 1 and 2-11 (ALT)•Results of cycle 1 and 2 were broadly consistent, when the difference in the-1-

to single-agent administration.

-HeadacheTransaminases (↑)•The pharmacokinetics of MBP-426 when combined with 5-FU and LV are comparable

AUC0-12h (µg.h/mL)

Safety (continued)

Cmax (µg/mL)• Phase Ib/II, open-label, non-randomized, single arm study of MBP-426 in combination withPharmacokinetics

Study Design (continued)

Study DesignIntroduction

170

226

Dose Level (mg/m²Conclusions• MBP-426 at 170 mg/m2 is the recommended dose for use in combination

with 5-FU/LV (de Gramont schedule) every 3 weeks.

• Treatment at this dose level was well tolerated• No peripheral neurotoxicity has been reported with this new oxaliplatin
formulation• Hints of efficacy were reported in patients with previous diseaseprogression and platinum resistance#03

Pancreas

5NO

Progression

#04

CRC4

G3 Back andAbdominal Pain

Progression

2

Dose level 170 mg/m• The co-administration of 5-FU and LV did not appear to alter theEfficacy
Stable disease was documented as best objective response (RECIST) in 4patients:#05

Cervix

4NOOn Study#06

Pancreas

3NO

Progression

#07

CRC

2NO

Progression• two patients with CRC, both of whom were oxaliplatin-resistant, and whoeach received a total of 4 cycles of treatment

#08

CRC

4NOOn Study• one patient with pancreas cancer, who received 5 cycles of treatment

#09

HyN

1NO

Non-compliance with protocol#10CRC2NOOn Study• one patient with cervical cancer, who was cisplatin-resistant, and who is stillon treatment after 4 cycles

pharmacokinetics of MBP-426• The phase II part has already started, looking for proof of concept insecond-line gastric and esophageal adenocarcinoma

REFERENCES
1. Sankhala, K.K., Mita, A.C., Adinin, R., Wood, L., Beeram, M., Bullock, S., Yamagata, N.,
Matsuno, K., Fujisawa, T., Phan, A. A phase I pharmacokinetic (PK) study of MBP-426, anovel liposome encapsulated oxaliplatin. J. Clin. Oncol. 2009; 27: 15s, #2535
2. Graham, M.A., Lockwood, G.F., Greenslade, D., Brienza, S., Bayssas, M., Gamelin E.
Clinical pharmacokinetics of oxaliplatin: a critical review. Clin. Cancer Res. 2009; 6:12051218