Eltrombopag with gemcitabine‐based chemotherapy in patients with advanced solid tumors: a randomized phase I study

Abstract

Preventing chemotherapy-induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine-based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag-treated patients versus 53 × 109/L and 103 × 109/L for placebo-treated patients in Groups A and B, respectively. No dose-limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose-escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.

Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice

“…TPO agonists or platelet transfusions have been occasionally used to increase platelet count in severely thrombocytopenic patients with cancer who receive nonmyeloablative chemotherapy, but, at present, the availability of data from controlled clinical trials to establish the harm or benefit of TPO agonists or platelet supplementation on long-term outcomes, including survival and quality of life, is limited. [57][58][59][60][61] Our present data support the concept that targeted hepatic THPO gene silencing is a feasible approach to therapeutic platelet count reduction within the safe range of hemostatic competence, and also support the hypothesis that platelets may contribute to cancer progression. Reducing platelet count within the hemostatic competence range vs inhibiting platelet functions with agents that impair all circulating platelets has other theoretical advantages, including instant reversibility.…”

Romiplostim for therapy‐related thrombocytopenia in pediatric malignancies

“…Eltrombopag, an oral TPO mimetic, is now FDA approved for use in children with cITP, but, like romiplostim, there are no reports on its use for TRT in children. Romiplostim and eltrombopag have been used safely and effectively for TRT in adults . Our series shows that romiplostim was well tolerated without adverse effects in all five pediatric patients.…”

Use of thrombopoietin receptor agonists after hematopoietic progenitor cell transplantation

“…18 There was also no difference in bleeding episodes or severity. 17,18 The consensus is that the available weak evidence does not support the use of TPO-RAs in solid tumor patients with chemotherapy related thrombocytopenia. 16 Recent evidence suggests that there may be a role for thrombopoietin (TRO) receptor agonists in the treatment of post HCT thrombocytopenia (Figure 1).…”

“…These medications have also been evaluated for the treatment and prevention of chemotherapy‐induced thrombocytopenia 16 . Randomized placebo‐controlled trials of TPO‐RAs for chemotherapy related thrombocytopenia did not meet the primary endpoint of difference in platelet count from day 1 cycle 2 to the platelet nadir in cycle 2 17 or show statistically significant difference in all‐cause mortality 18 . There was also no difference in bleeding episodes or severity 17,18 .…”