Chemotherapy-induced Thrombocytopenia
Conditions
Keywords
CIT, Thrombocytopenia
Brief summary
Phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of avatrombopag in subjects with chemotherapy-induced thrombocytopenia receiving chemotherapy for the treatment of ovarian, lung (small cell and non-small cell) and bladder cancer.
Detailed description
Subjects will receive placebo controlled test treatment for one cycle of chemotherapy followed by an observational cycle. Subjects will have the option to continue into an open label extension period for all remaining chemotherapy cycles within the current regimen. After the follow-up visit, all subjects will continue to a long-term safety follow-up period.
Interventions
DRUGAvatrombopag
Oral avatrombopag tablet
DRUGPlacebo Oral Tablet
Placebo comparator tablet
Sponsors
Sobi, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women greater than or equal to 18 years of age; * A diagnosis of ovarian, lung (small cell or non-small cell) or bladder cancer requiring systemic chemotherapy * Participant receiving a chemotherapy regimen given in a 21 or 28-day cycle, 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; * Participant experienced severe thrombocytopenia, defined as 2 platelet counts \<50 x 109/L measured at least 24 hours apart, during the qualifying chemotherapy cycle, of their current chemotherapy regimen * ECOG performance status \<=2
Exclusion criteria
* Participant has experienced \>=Grade 2 CIT other than during the current chemotherapy treatment regimen within 6 months of Screening; * Participant has any history of hematologic malignancies, including leukemia, myeloma, myeloproliferative disease, lymphoma, or myelodysplastic diseases; * Participant has received \>2 previous lines of chemotherapy or is receiving whole brain radiation during the study treatment period; * Participant has a known medical history of genetic prothrombotic syndromes * Participant has a history of arterial or venous thrombosis within 3 months of screening; * Use of vitamin K antagonists; * Participant has previously received a thrombopoietin receptor agonist or recombinant human thrombopoietin for the treatment of CIT within 3 months of screening
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Subjects Who do Not Require Platelet Transfusion, Dose Reduction in Chemotherapy by 15%, or Chemotherapy Delay by >=4 Days | Randomization up to 33 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Severe Thrombocytopenia Defined as a Platelet Count <50 x 10^9/L | Randomization up to 33 days | The duration of severe thrombocytopenia is defined as the total number of days with a platelet count \<50×10\^9/L during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2. |
| Change in Platelet Count From Baseline (Nadir) | Randomization up to 33 days | Comparison of avatrombopag 60 mg vs. placebo, adjusted for the number of chemotherapy agents currently receiving per IWRS (1, ≥2). Cycle X nadir is defined as the lowest platelet count value prior to the first dose of study drug; Cycle X+1 nadir is defined as the lowest platelet count value during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day in Cycle X+2. |
| Percentage of Subjects Who Did Not Have Major or Non-major Clinically Relevant Bleeding During the Period After Post-chemotherapy Study Drug Treatment in Cycle X+1 Through Chemotherapy Day of Cycle X+2. | Randomization up to 33 days | — |
Countries
China, Hungary, Poland, Russia, Serbia, Ukraine, United States
Participant flow
Recruitment details
This was a Phase 3, randomized, double- blind, placebo controlled study of the efficacy and and safety of avatrombopag in subjects with chemotherapy induced thrombocytopenia and non active non-hematologic cancers. The study was conducted by qualified investigators at 71 sites in China, Hungary, Poland, Russia, Serbia, Ukraine, and the United States. The first subject was enrolled 12October2018.
Pre-assignment details
The study was conducted by qualified investigators at 71 sites in China, Hungary, Poland, Russia, Serbia, Ukraine, and the United States. The first subject was enrolled 12October2018.
Participants by arm
| Arm | Count |
|---|---|
| Avatrombopag Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment.
Avatrombopag: Oral avatrombopag tablet | 82 |
| Placebo Study is 2:1 randomization ratio (avatrombopag to placebo). Investigational product administered orally once daily for 5 days prior to chemotherapy and 5 days following chemotherapy treatment.
Placebo Oral Tablet: Placebo comparator tablet | 40 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Other | 3 | 2 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 1 |
Baseline characteristics
| Characteristic | Avatrombopag | Placebo | Total |
|---|---|---|---|
| Age, Continuous Age at Enrollment | 61.0 years STANDARD_DEVIATION 10.08 | 60.8 years STANDARD_DEVIATION 10.41 | 61.0 years STANDARD_DEVIATION 10.15 |
| Baseline Platelet Count (x10⁹/L) | 29.6 platelets x10⁹/L STANDARD_DEVIATION 13.66 | 33.0 platelets x10⁹/L STANDARD_DEVIATION 11.49 | 30.7 platelets x10⁹/L STANDARD_DEVIATION 13.04 |
| BMI (kg/m²) | 27.7 kg/m² STANDARD_DEVIATION 6.56 | 28.5 kg/m² STANDARD_DEVIATION 5.58 | 27.9 kg/m² STANDARD_DEVIATION 6.24 |
| ECOG Performance Status Subjects with ECOG Score 0 | 21 Participants | 8 Participants | 29 Participants |
| ECOG Performance Status Subjects with ECOG Score 1 | 60 Participants | 31 Participants | 91 Participants |
| ECOG Performance Status Subjects with ECOG Score 2 | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 37 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 3 Participants | 7 Participants |
| Height (cm) | 166.3 cm STANDARD_DEVIATION 10.17 | 166.2 cm STANDARD_DEVIATION 10.32 | 166.3 cm STANDARD_DEVIATION 10.18 |
| Number of Eligible Chemotherapy Agents Currently Receiving per IWRS Subjects Receiving 1 Agent | 40 Participants | 20 Participants | 60 Participants |
| Number of Eligible Chemotherapy Agents Currently Receiving per IWRS Subjects Receiving ≥ 2 Agents | 42 Participants | 20 Participants | 62 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 77 Participants | 37 Participants | 114 Participants |
| Sex: Female, Male Female | 43 Participants | 22 Participants | 65 Participants |
| Sex: Female, Male Male | 39 Participants | 18 Participants | 57 Participants |
| Weight (kg) | 76.2 kg STANDARD_DEVIATION 17.73 | 78.8 kg STANDARD_DEVIATION 17.64 | 77.0 kg STANDARD_DEVIATION 17.67 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 82 | 0 / 40 |
| other Total, other adverse events | 71 / 82 | 36 / 40 |
| serious Total, serious adverse events | 16 / 82 | 8 / 40 |
Outcome results
Primary
Percentage of Subjects Who do Not Require Platelet Transfusion, Dose Reduction in Chemotherapy by 15%, or Chemotherapy Delay by >=4 Days
Time frame: Randomization up to 33 days
Population: All randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avatrombopag | Percentage of Subjects Who do Not Require Platelet Transfusion, Dose Reduction in Chemotherapy by 15%, or Chemotherapy Delay by >=4 Days | 57 Participants |
| Placebo | Percentage of Subjects Who do Not Require Platelet Transfusion, Dose Reduction in Chemotherapy by 15%, or Chemotherapy Delay by >=4 Days | 29 Participants |
p-value: 0.718695% CI: [-21.7, 15.6]Cochran-Mantel-Haenszel
Secondary
Change in Platelet Count From Baseline (Nadir)
Comparison of avatrombopag 60 mg vs. placebo, adjusted for the number of chemotherapy agents currently receiving per IWRS (1, ≥2). Cycle X nadir is defined as the lowest platelet count value prior to the first dose of study drug; Cycle X+1 nadir is defined as the lowest platelet count value during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day in Cycle X+2.
Time frame: Randomization up to 33 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Avatrombopag | Change in Platelet Count From Baseline (Nadir) | 51.5 Platelets x 10^9/L | Standard Deviation 61.85 |
| Placebo | Change in Platelet Count From Baseline (Nadir) | 29.1 Platelets x 10^9/L | Standard Deviation 39.48 |
Secondary
Duration of Severe Thrombocytopenia Defined as a Platelet Count <50 x 10^9/L
The duration of severe thrombocytopenia is defined as the total number of days with a platelet count \<50×10\^9/L during the period after post-chemotherapy study drug treatment in Cycle X+1 through Chemotherapy Day of Cycle X+2.
Time frame: Randomization up to 33 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Avatrombopag | Duration of Severe Thrombocytopenia Defined as a Platelet Count <50 x 10^9/L | 4.6 Days | Standard Deviation 5.53 |
| Placebo | Duration of Severe Thrombocytopenia Defined as a Platelet Count <50 x 10^9/L | 4.7 Days | Standard Deviation 6.56 |
p-value: 0.8372Van Elteren Test
Secondary
Percentage of Subjects Who Did Not Have Major or Non-major Clinically Relevant Bleeding During the Period After Post-chemotherapy Study Drug Treatment in Cycle X+1 Through Chemotherapy Day of Cycle X+2.
Time frame: Randomization up to 33 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avatrombopag | Percentage of Subjects Who Did Not Have Major or Non-major Clinically Relevant Bleeding During the Period After Post-chemotherapy Study Drug Treatment in Cycle X+1 Through Chemotherapy Day of Cycle X+2. | 82 Participants |
| Placebo | Percentage of Subjects Who Did Not Have Major or Non-major Clinically Relevant Bleeding During the Period After Post-chemotherapy Study Drug Treatment in Cycle X+1 Through Chemotherapy Day of Cycle X+2. | 40 Participants |