E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chemotherapy-Induced Thrombocytopenia in Subjects With Active Non-Hematological Cancers |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10043555 |
E.1.2 | Term | Thrombocytopenias |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039884 |
E.1.2 | Term | Secondary thrombocytopenia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024922 |
E.1.2 | Term | Low platelets |
E.1.2 | System Organ Class | 100000004848 |
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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 |
To evaluate the efficacy of avatrombopag in increasing platelet counts and therefore preventing the need for a platelet transfusion or chemotherapy dose
reduction or delay in subjects with CIT. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of avatrombopag in subjects with CIT, and
• To investigate the effect of avatrombopag on bleeding in subjects with CIT. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria will be eligible to participate in the study:
1. Subject is ≥18 years of age at the time of informed consent;
2. Subject with a diagnosis with ovarian cancer, lung cancer (small cell or non-small cell), or bladder cancer, requiring systemic chemotherapy;
3. Subject is currently receiving a chemotherapy regimen given in a 21-day or 28-day cycle (other chemotherapy cycle lengths are not allowed), including 1 or more of the following agents or class of agents:
-Nucleoside analog, including gemcitabine and fluorouracil;
-Carboplatin or cisplatin;
-Anthracycline; or
-Alkylating agent;
4. Subject experienced severe thrombocytopenia, defined as 2 platelet counts <50 × 109/L measured at least 24 hours apart, during the qualifying chemotherapy cycle (Cycle X), of their current chemotherapy regimen. Platelet counts obtained per standard of care during Cycle X prior to consent may be used;
5.Subject is planned to receive the same chemotherapy regimen and the same dose(s) on Chemotherapy Day (Days 1-3) of Cycle X+1 as was given in the qualifying chemotherapy Cycle X;
6. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2;
7. Subject has a life expectancy >12 weeks at Screening and is able to receive at least 2 additional cycles of the current chemotherapy regimen;
8. Females of childbearing potential must agree to use a highly effective method of contraception (eg, total abstinence; an intrauterine device; hormonal contraceptive given orally, by injection, or by implant; double barrier contraception (i.e., condom + diaphragm); or has a vasectomized
partner with confirmed azoospermia) throughout the entire study period and for 30 days after investigational product (IP) discontinuation. If currently abstinent, the subject must agree to use an effective method as described above if she becomes sexually active during the study period or for 30 days after IP discontinuation. Male subjects must be either surgically sterile or agree to use a double barrier contraception method (combination of male condom with either cap, diaphragm, or sponge with a spermicide) throughout the entire study period and for 30 days after IP discontinuation;
9. Subject is willing and able to comply with all aspects of the protocol; and
10. Subject must provide written informed consent.
Inclusion Criteria for Subjects to Continue Into the Optional Open-Label Extension Period
Subjects who meet all of the following criteria will be eligible to continue into the optional
Open-Label Extension (OLE) Period:
1. Subject is currently receiving the same chemotherapy agents as were given in the qualifying chemotherapy Cycle X;
2. Subject has an ECOG performance status ≤2;
3. Females of childbearing potential must agree to use a highly effective method of contraception as previously defined.
Male subjects must be either surgically sterile or agree to use a double barrier contraception method (combination of male condom with either cap, diaphragm, or sponge with a spermicide) throughout the entire study period and for 30 days after IP discontinuation;
4. Subject is willing and able to comply with all aspects of the protocol; and
5. Subject must provide consent to continue into the OLE Period. |
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E.4 | Principal exclusion criteria |
1. Subject has experienced ≥ Grade 2 CIT with a platelet count <75 × 10^9/L (other than during the current chemotherapy treatment regimen) within 6 months of Screening;
2. Subject has a platelet count >175 × 10^9/L at Visit 2 (-1 day);
3. Subject with any history of hematologic malignancies, including leukemia, myeloma, myeloproliferative disease, lymphoma, or myelodysplastic diseases;
4. Subject who received >2 previous lines of chemotherapy (adjuvant/neoadjuvant therapy is considered a previous line; immunotherapy alone is not considered a previous line) or is receiving whole brain radiation during the study treatment period;
5. Subject with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal or total bilirubin ≥3 × upper limit of normal;
6. Subject has a known medical history of human immunodeficiency virus;
7. Subject has any known clinically significant acute or active bleeding (eg, gastrointestinal or central nervous system) within 7 days of Screening;
8. Subject has a known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden, prothrombin G20210A, or ATIII deficiency);
9. Subject has a recent history (within 3 months of Screening) of significant cardiovascular disease (eg, congestive heart failure exacerbation, arrhythmia known to increase the risk of thromboembolic events [eg, atrial fibrillation], coronary artery stent placement, angioplasty, or coronary artery bypass graft);
10. Subject has a history of arterial or venous thrombosis within 3 months of Screening;
11. Subject has used vitamin K antagonists within 7 days of Screening (use of low molecular weight heparin, Xa inhibitors, or thrombin inhibitors is allowed);
12. Subject has a history of chronic platelet or bleeding disorders or thrombocytopenia due to an etiology other than CIT (eg, chronic liver disease or immune thrombocytopenia purpura);
13. Subject has used moderate or strong inducers of cytochrome P450 (CYP)2C or CYP3A4/5 within 7 days of Screening;
14. Subject has received a thrombopoietin receptor agonist (eg, eltrombopag or romiplostim) or recombinant human thrombopoietin for the treatment of CIT within 3 months of Screening;
15. Subject received a platelet transfusion within 72 hours of randomization;
16. Subject is unable to take oral medication;
17. Subject has any history of a concomitant medical condition that, in the opinion of the Investigator, would compromise the subject’s ability to safely complete the study, such as unstable angina, renal failure requiring hemodialysis, or active infection requiring intravenous antibiotics;
18. Female subjects who are lactating or pregnant at Screening or the Baseline Visit (as documented by a positive serum or urine beta-human chorionic gonadotropin [β-hCG] test);
19. Subject has hypersensitivity to avatrombopag or any of its excipients; or
20. Subject is currently enrolled in another clinical study with any investigational drug or device within 30 days of Screening; however, participation in observational studies is permitted.
Exclusion Criteria for Subjects to Continue Into the Optional Open-Label Extension Period Subjects who meet any of the following criteria will be excluded from continuing into the optional OLE Period:
1. Subject has a platelet count >175 × 10^9/L on the scheduled first day of dosing of avatrombopag prior to chemotherapy;
2. Subject with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal or total bilirubin ≥3 × upper limit of normal;
3. Subject has any known clinically significant acute or active bleeding (eg, gastrointestinal or central nervous system) within 7 days of pre-chemotherapy IP treatment in OLE cycles;
4. Subject has used vitamin K antagonists within 7 days of pre-chemotherapy IP treatment in Cycle X + 3 (use of low molecular weight heparin, Xa inhibitors, or thrombin inhibitors is allowed);
5. Subject has used moderate or strong inducers of CYP2C or CYP3A4/5 within 7 days of pre-chemotherapy IP treatment in OLE cycles;
6. Subject is unable to take oral medication;
7. Female subjects who are lactating or pregnant (as documented by a positive urine or serum test) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of responders who meet all of the following criteria during the period after post-chemotherapy IP treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2:
• Not requiring a platelet transfusion;
• Not requiring a chemotherapy dose reduction by ≥15% due to thrombocytopenia; and
• Not requiring a chemotherapy delay by ≥4 days due to thrombocytopenia. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Duration of severe thrombocytopenia defined as a platelet count <50 × 109/L during the period after post-chemotherapy IP treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2;
• Change in platelet count from baseline (qualifying chemotherapy cycle [Cycle X]) (nadir) to Cycle X + 1 (nadir);
• Proportion of subjects who do not have major or non-major clinically relevant bleeding during the period after post-chemotherapy IP treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2; and
• Proportion of subjects who do not receive platelet transfusion during the period after postchemotherapy IP treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | No |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
Russian Federation |
Serbia |
Ukraine |
United States |
Hungary |
Poland |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of study (“study completion”) is defined as the date of the last protocol-specified visit/assessment (including telephone contact) for the last subject in the Long-Term Follow-Up Period. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 8 |