| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chemotherapy induced thrombocytopenia |
|
| E.1.1.1 | Medical condition in easily understood language |
| low platelet count, induced by chemotherapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10043554 |
| E.1.2 | Term | Thrombocytopenia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of Phase I of the study is to assess the safety and tolerability of eltrombopag compared to placebo when administered to subjects with solid tumors receiving gemcitabine monotherapy or the combination of gemcitabine plus carboplatin or cisplatin.
The primary objective of Phase II of the study is to evaluate the efficacy of the dose of eltrombopag selected from Phase I compared to placebo on platelet counts when administered to subjects with solid tumors receiving gemcitabine monotherapy or the combination of gemcitabine plus carboplatin or cisplatin who experienced thrombocytopenia in a previous cycle. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of phase I :
• To evaluate the effect of eltrombopag compared to placebo on platelet pharmacodynamics;
• To evaluate the effect of eltrombopag compared to placebo on chemotherapy dose intensity and dose delay; and
• To evaluate the relationship between plasma eltrombopag concentrations and pharmacodynamics.
Secondary objectives of phase II:
• To assess the safety and tolerability of eltrombopag compared to placebo;
• To evaluate the effects of eltrombopag compared to placebo on Day 8 (and Day 15 for subjects receiving gemcitabine monotherapy) pre-chemotherapy platelet counts;
• To evaluate the effect of eltrombopag compared to placebo on platelet pharmacodynamics;
• To evaluate the effect of eltrombopag compared to placebo on chemotherapy dose intensity and dose delay of chemotherapy;
For remaining secondary objectives please refer to page 22 of protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in Phase I and II of the study must meet all of the following criteria:
1. Signed written informed consent.
2. Age ≥ 18 years.
3. Subjects with confirmed solid tumor and scheduled to receive at least two cycles of either gemcitabine monotherapy OR gemcitabine in combination with carboplatin or cisplatin at the same dosages and schedule in the study. Novel anticancer agents (e.g. bevacizumab, erlotinib) may be allowed if considered the standard treatment by the investigator.
• Note: For patients scheduled to receive any novel anticancer agents (e.g. bevacizumab, erlotinib), consultation and approval from the GSK medical monitor should occur before the subject is enrolled into the study.
4. Life expectancy of at least 3 months, in the opinion of the investigator.
5. ECOG-Zubrod performance status ≤ 2 (refer to Appendix 5, pg 110 of protocol).
6. For Phase I: Pre-chemotherapy platelet count ≤ 300 Gi/L in the screening period before the subject start their first planned cycle of treatment with gemcitabine monotherapy OR gemcitabine in combination with carboplatin or cisplatin in the study.
7. For Phase II (Part 1 and 2): Subjects must meet one of the following platelet count entry criteria:
a. Platelet count < 150 Gi/L in the screening period as measured within 3 days before Day 1of the first cycle in this disease setting,
OR
b. Subjects started chemotherapy for this disease setting and had platelet count < 150 Gi/L on Day 1 in the preceding cycle before entry into the study,
OR
c. Platelet count < 100 Gi/L at Day 8 in the preceding cycle before entry into the study,
OR
d. Platelet count < 100 Gi/L at Day 15 in the preceding cycle before entry into the study (for subjects receiving Gemcitabine monotherapy)
.Also see Section 6.2.2 of Protocol for guidelines for chemotherapy dose adjustments.
8. Subjects with previous chemotherapy treatment in a previous disease setting are allowed provided they have recovered from chemotherapy related toxicity except alopecia (and the lab parameters mentioned in Inclusion criteria in #9).
9. Adequate baseline organ function defined by the criteria given in table (refer to pg 40 of protocol)
Subjects with AST, ALT or bilirubin values outside the range(s) in the table due to Gilbert’s syndrome or asymptomatic gall stones are not excluded.
10. Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to randomization and agree to use effective contraception, as defined in Section 8.4.2 of protocol, during the study and for 4 weeks following the last dose of investigational product.
11. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 8.4.2 from 2 weeks prior to randomization until 13 weeks after the last dose of study treatment.
12. Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
|
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Lactating females.
2. Pre-existing cardiovascular disease (congestive heart failure, New York Heart Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), unstable angina, or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block) at study
entry, or myocardial infarction within the preceding 6 months. Subjects with a pacemaker or defibrillator are not excluded provided that their cardiac function is within normal ranges.
• Note: For patients with pre-existing NYHA Grade II cardiovascular disease, the investigator should consult with GSK medical monitor before enrolling the subject into the study.
3. Patients with known factor V leiden, antiphospholipid antibody syndrome, prothrombin gene mutations, ATIII deficiency, protein C deficiency, protein S deficiency OR recent history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism) within the preceding 6 months.
• Note: for patients other with known risk factors for thromboembolism e.g., diabetes, hypercholesterolemia, recent major surgery etc., the investigator should consult with GSK medical monitor before enrolling the patient into the study and all risk factors should be documented in the CRF.
4. Prior surgery within two weeks before study randomization or radiotherapy (RT) within four weeks before study randomization. Subjects with prior surgery or RT are not permitted into the study unless they have completely recovered from surgery and/or acute RT toxicity except for alopecia.
• Note: patients with minor surgeries or outpatient procedures (e.g. insertion of central venous catheter) are immediately allowed in the study provided that there were no complications from the procedure or surgery.
5. History of prior radiotherapy to more than 20% bone marrow bearing sites.
6. History of platelet agglutination abnormality, platelet disorders or dysfunction or bleeding disorder that prevents reliable measurement of platelet counts.
7. Subjects with a history of CNS metastases or clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by CT or MRI brain scan unless properly treated. Subjects with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to randomization will be excluded.
• Treated brain metastases are defined
• Having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed.
• Treatment for brain metastases may include whole brain radiotherapy
(WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a
combination as deemed appropriate by the treating physician.
Note: if subject has performed a CT scan immediately prior to the screening period and CT could not be repeated, an MRI should be performed in the screening period to exclude the development of brain metastases and/or the progression of the pre-existing brain metastatic lesion(s).
8. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational product in the study. Concurrent participation in another interventional clinical trial or administration of any investigational drug during the study is also not permitted.
9. A known immediate or delayed hypersensitivity reaction or idiosyncrasy that, in the opinion of the Investigator or GSK Medical Monitor is due to drugs chemically related to eltrombopag or excipients (e.g. mannitol).
10. Subjects with known Hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV). Subjects with Gilbert’s Syndrome are permitted into the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: Primary Endpoint
• Safety and tolerability of eltrombopag as assessed by evaluating adverse events (AE) reporting, and changes from baseline in other safety parameters including clinical laboratory values.
Phase II: Primary Endpoint
• Effect of eltrombopag compared to placebo on the scheduled Day 1 prechemotherapy
platelet counts will be evaluated across all cycles
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For 21-day cycle: Screening, Day 1, 4, 8, 15, 17 of each cycle, conclusion/early withdrawal visit, 30-day follow-up
For 28-day cycle: Screening, Day 1, 4, 8, 15, 22, 24 of each cycle, conclusion/early withdrawal visit, 30-day follow-up
|
|
| E.5.2 | Secondary end point(s) |
Phase I: Secondary Endpoints
• Platelet pharmacodynamics for eltrombopag and placebo treated subjects will be assessed by evaluating the:
-Pre-chemotherapy platelet counts
-Average platelet counts
-Platelet nadir count
-The area under platelet-time course data
-Grade of thrombocytopenia
-Duration of thrombocytopenia
-Time to platelet nadir
-Time to recovery from platelet nadir
• The effects of eltrombopag on chemotherapy dose will be assessed by evaluating the dose intensity of chemotherapy and chemotherapy dose delay(s) for eltrombopag and placebo treated subjects; and
• Plasma eltrombopag concentrations and the relationship between plasma concentrations and pharmacodynamics.
Phase II: Secondary Endpoints
• Safety and tolerability of eltrombopag as assessed by evaluating adverse events (AE), and changes from baseline in other safety data including clinical laboratory parameters;
• Effect of eltrombopag compared to placebo on the scheduled Day 8 (and Day15 for subject receiving gemcitabine monotherapy) pre-chemotherapy platelet counts will be evaluated across all cycles;
• Platelet pharmacodynamics for eltrombopag and placebo treated subjects will be assessed by evaluating the:
-Average platelet counts
-Platelet nadir counts
-The area under platelet-time course data
-Grade of thrombocytopenia
-Duration of thrombocytopenia
-Time to platelet nadir
-Time to recovery from platelet nadir
• The effects of eltrombopag on chemotherapy dose will be assessed by evaluating dose intensity of chemotherapy and chemotherapy dose delay(s) for eltrombopag and placebo treated subjects;
• Incidence and severity of bleeding, as assessed by the WHO bleeding scale for eltrombopag and placebo treated subjects;
• The number of eltrombopag and placebo treated subjects requiring platelet transfusion(s);
• Plasma eltrombopag concentrations and the relationship between plasmaconcentrations and pharmacodynamics |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For 21-day cycle: Screening, Day 1, 4, 8, 15, 17 of each cycle, conclusion/early withdrawal visit, 30-day follow-up
For 28-day cycle: Screening, Day 1, 4, 8, 15, 22, 24 of each cycle, conclusion/early withdrawal visit, 30-day follow-up
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.1.7.1 | Other trial design description |
| Two phase, sequential cohort study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Finland |
| Germany |
| Greece |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Subjects who have completed their chemotherapy regimen and have not progressed by the time of the 30-day follow-up visit, will continue to be followed up . The investigator is requested to provide updates on the status of the disease following end of investigational product on average every 3-4 months for up to 1 year, unless disease has progressed or death has occurred prior to the 1 year. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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