Efficacy and Safety of Eltrombopag, a Novel Oral Platelet Growth Factor, on Platelet Counts in Patients With Cancer Receiving

Carboplatin/Paclitaxel Chemotherapy
A. Baranwal,1 J. L. A. Fraser,1 D. Jayawardene,1 A. Jagiello-Gruszfeld,2 I. Bondarenko,3 J. L. Mendoza4
GlaxoSmithKline, Collegeville, PA, USA; 2ZOZ MSWiA z Warminsko-Mazurskim Centrum Onkologii, Olsztyn, Poland; 3 Radiodiagnostic and Radiotherapy Chair of Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine; 4Salem Research Institute, Inc., Salem, VA, USA.
1

INTRODUCTION
Chemotherapy-induced thrombocytopenia (CIT) is a significant source of morbidity for many cancer patients Chemotherapy dose delay and reduction due to thrombocytopenia (TCP) is common Eltrombopag is the first oral platelet growth factor for the treatment of TCP Eltrombopag is a thrombopoietin receptor agonist that boosts platelet production and may reduce the severity of TCP in patients receiving chemotherapy Eltrombopag has previously been shown to increase platelet counts in healthy volunteers and in patients with refractory idiopathic thrombocytopenic purpura and hepatitis C-associated TCP This analysis assessed the safety and efficacy of eltrombopag in cancer patients receiving chemotherapy at risk for CIT

METHODS: PATIENTS
Inclusion Criteria Patients were to have the following: Advanced solid tumors Received carboplatin/paclitaxel Study Populations Modified intent-to-treat population (mITT): Patients who were randomized and administered at least 1 dose of the study treatment in Cycle 1 and for whom baseline and at least 1 on-therapy platelet count was collected Safety population: Patients who received at least 1 dose of study medication during any cycle

RESULTS: SAFETY
The prevalence of adverse events in patients who received placebo, eltrombopag 50 mg, eltrombopag 75 mg, or eltrombopag 100 mg were 83%, 75%, 68%, and 87%, respectively (Table 2) The prevalence of serious adverse events in patients who received placebo, eltrombopag 50 mg, eltrombopag 75 mg, or eltrombopag 100 mg were 13%, 9%, 7%, and 13%, respectively (Table 2)
TABLE 2. OVERALL SUMMARY OF ADVERSE EVENTS DURING 2 CYCLES OF TREATMENT
Placebo (n = 46) n (%) Events 38 (83) 6 (13) 13 (28) 4 (9) 218 6 30 4 Eltrombopag 50 mg (n = 44) n (%) Events 33 (75) 4 (9) 7 (16) 0 (0) 227 6 19 0 Eltrombopag 75 mg (n = 44) n (%) Events 30 (68) 3 (7) 11 (25) 4 (9) 137 6 26 4 Eltrombopag 100 mg (n = 46) n (%) Events 40 (87) 6 (13) 14 (30) 11 (24) 210 6 17 11 Total (N = 180) n (%) Events 141 (78) 792 19 (11) 45 (25) 19 (11) 24 92 19

Characteristic Any AE Serious AE Drug-related AE AE that lead to withdrawal

RESULTS: BASELINE CHARACTERISTICS PRIMARY OBJECTIVE

To evaluate the efficacy of oral eltrombopag compared with placebo in Cycle 2 of carboplatin/paclitaxel chemotherapy, administered to patients with an advanced solid tumor Patients were primarily female (58%) and had a median age of 58 years (Table 1) 78% of patients had baseline platelet counts 250,000/L (Table 1) Most patients had either non-small cell lung (61%) or ovarian (26%) tumors (Table 1)
TABLE 1. PATIENT CHARACTERISTICS

Serious AE that lead to withdrawal Ongoing AE at the end of study/withdrawal

AE, adverse event.

1 (2)

0 (0)

2 (5)

4 (9)

7 (4)

11 (24)

25

12 (27)

20

9 (20)

11

14 (30)

20

46 (26)

76

The most common adverse events recorded during 2 cycles of treatment are presented in Table 3
TABLE 3. SUMMARY OF THE MOST COMMON ADVERSE EVENTS DURING 2 CYCLES OF TREATMENT
Placebo (n = 46) 38 (83) 15 (33) 10 (22) 14 (30) 8 (17) 7 (15) 4 (9) 4 (9) 3 (7) 5 (11) 5 (11) 7 (15) 3 (7) 3 (7) 1 (2) 3 (7) 1 (2) 0 (0) 3 (7) Eltrombopag 50 mg (n = 44) 33 (75) 16 (36) 17 (39) 6 (14) 4 (9) 7 (16) 8 (18) 5 (11) 5 (11) 1 (2) 3 (7) 3 (7) 5 (11) 5 (11) 1 (2) 4 (9) 6 (14) 4 (9) 4 (9) Eltrombopag 75 mg (n = 44) 30 (68) 13 (30) 8 (18) 9 (20) 3 (7) 4 (9) 4 (9) 4 (9) 5 (11) 6 (14) 1 (2) 1 (2) 2 (5) 1 (2) 4 (9) 0 (0) 1 (2) 2 (5) 0 (0) Eltrombopag 100 mg (n = 46) 40 (87) 10 (22) 12 (26) 10 (22) 8 (17) 3 (7) 4 (9) 5 (11) 3 (7) 3 (7) 5 (11) 2 (4) 2 (4) 3 (7) 6 (13) 3 (7) 2 (4) 3 (7) 2 (4) Total (N = 180) 141 (78) 54 (30) 47 (26) 39 (22) 23 (13) 21 (12) 20 (11) 18 (10) 16 (9) 15 (8) 14 (8) 13 (7) 12 (7) 12 (7) 12 (7) 10 (6) 10 (6) 9 (5) 9 (5)

METHODS: STUDY DESIGN

Characteristic Placebo (n = 45) 58 (23-73) 29 (64.4) 16 (35.6) 37 (82.2) 20 (44.4) 24 (53.3) 1 (2.2) 27 (60.0) 13 (28.9) 5 (11.1)

Eltrombopag 50 mg (n = 41) 58 (35-75) 20 (48.8) 21 (51.2) 25 (61.0) 20 (48.8) 21 (51.2) 0 (0.0) 26 (63.4) 8 (19.5) 7 (17.1)

Eltrombopag 75 mg (n = 41) 59 (33-75) 27 (65.9) 14 (34.1) 35 (85.4) 16 (39.0) 25 (61.0) 0 (0.0) 25 (61.0) 10 (24.4) 6 (14.6)

Eltrombopag 100 mg (n = 43) 59 (34-81) 22 (51.2) 21 (48.8) 35 (81.4) 14 (32.6) 29 (67.4) 0 (0.0) 25 (58.1) 14 (32.6) 4 (9.3)

Total (N = 170) 58 (23-81) 98 (57.6) 72 (42.4) 132 (77.6) 70 (41.2) 99 (58.2) 1 (0.6) 103 (60.6) 45 (26.5) 22 (12.9)

Characteristic, n (%) Any Nausea Alopecia Neutropenia Vomiting Leukopenia Arthralgia Fatigue Diarrhea Anemia

Randomized, double-blind, multicenter phase II study Placebo and eltrombopag 50, 75, and 100 mg were administered orally for 10 days (Days 2-11) of each cycle Carboplatin (AUC 5-6 IV over 15-30 min) and paclitaxel (175-225 mg/m2 IV over 3 hours) were administered on Day 1 and repeated every 21 days Patients received a maximum of 8 cycles of placebo or eltrombopag treatment
Figure 1. Study design.
Begin Cycle 2 (Day 22) Carboplatin and paclitaxel (Day 1) End Cycle 1 (Day 21)

Age, y Median (range) Gender, n (%) Female Male Platelet count 250,000/L, n (%) ECOG/Zubrod score, n (%) 0 1 2 Tumor type, n (%) Non-small cell lung Ovary Other
ECOG, Eastern Cooperative Oncology Group.

Constipation

RESULTS: DR UG DOSES
All groups received comparable baseline doses of carboplatin and paclitaxel Mean doses of carboplatin for the placebo and eltrombopag 50-, 75-, and 100-mg arms were 556.1, 545.8, 567.7, and 531.8 mg, respectively Mean doses of paclitaxel for the placebo and eltrombopag 50-, 75-, and 100-mg arms were 320.7, 327.8, 321.1, and 313.8 mg, respectively

Pain in extremity Myalgia Pyrexia Thrombocythemia Asthenia Headache Anorexia Cough

Eltrombopag or placebo (Days 2-11)

METHODS: PRIMARY STUDY ENDPOINT

Change in platelet count from Day 1 in Cycle 2 to the platelet nadir in Cycle 2 Platelet nadir is defined as the minimum platelet count during Days 8-18

RESULTS: EFFICACY
All patients who received eltrombopag had higher platelet counts at the end of Cycles 1 and 2 (Figure 2A and 2B, respectively) compared to those who received placebo
Figure 2A. Mean (SD) platelet counts by visit in Cycle 1.
700

Figure 2B. Mean (SD) platelet counts by visit in Cycle 2.

700

Platelet count (x1,000/L)

500 400 300 200 100 0 1 2 5 8 11 15 18

Placebo Eltrombopag 50 mg Eltrombopag 75 mg Eltrombopag 100 mg

Platelet count (x1,000/L)

METHODS: SECONDARY STUDY ENDPOINTS

Change in platelet count from Day 1 in Cycle 1 to the platelet nadir in Cycle 1 Safety and tolerability as indicated by physical exam, laboratory tests, and adverse event reporting

600

600 500 400 300 200 100 0 1 2 5 8 11 15 18

Placebo Eltrombopag 50 mg Eltrombopag 75 mg Eltrombopag 100 mg

Day

Day

CONCLUSIONS
Eltrombopag 50, 75, and 100 mg resulted in a dose-dependent increase in platelet counts from Day 8 to the end of Cycles 1 and 2 In this study, the safety profile of eltrombopag was comparable to placebo Pharmacodynamic data from this study will be used to design future studies to understand the optimal eltrombopag schedules for improving platelet nadir counts following chemotherapy

Poster presented at the 20th Anniversary International Multinational Association of Supportive Care in Cancer (MASCC)/International Society for Oral Oncology (ISOO) Symposium, June 28-30, 2007, St. Gallen, Switzerland.