Chemotherapy-induced Thrombocytopenia
Conditions
Keywords
Chemotherapy Induced Thrombocytopenia, Gastrointestinal Cancer, Colorectal Cancer, Pancreatic Cancer
Brief summary
Study of Romiplostim for Chemotherapy-induced Thrombocytopenia in Adult Subjects with Gastrointestinal, Pancreatic, or Colorectal Cancer
Detailed description
RECITE: A phase 3 Randomized Placebo-controlled Double-blind Study of Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in Patients Receiving Oxaliplatin-based Chemotherapy for Treatment of Gastrointestinal, Pancreatic, or Colorectal Cancer
Interventions
BIOLOGICALRomiplostim
This study is designed to study Romiplostim for the treatment of chemotherapy-induced thrombocytopenia (CIT) in patients receiving chemotherapy for the treatment of gastrointestinal/colorectal/pancreatic cancer.
OTHERPlacebo
Placebo Comparator
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent prior to initiation of any study specific activities/procedures or subject's legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent. * Males or females greater than or equal to 18 years of age at signing of the informed consent. * Histologically or cytologically confirmed diagnosis of gastrointestinal, pancreatic, or colorectal adenocarcinoma, defined as cancers of the esophagus (including esophagogastric junction \[EGJ\] cancer), stomach, pancreas, colon, or rectum. Tumor stage will not affect eligibility. * Subjects must be receiving 1 of the following regimens: An oxaliplatin-based chemotherapy regimen, containing 5 FU or capecitabine plus oxaliplatin (irinotecan may be added for FOLFIRINOX or FOLFOXIRI) on a 14- or 21 day schedule, respectively; OR, subjects must have chemotherapy-induced thrombocytopenia from a non-protocol chemotherapy regimen, planning to start treatment with one of the protocol chemotherapy regimens which has been delayed greater than or equal to one week due to chemotherapy-induced thrombocytopenia. Note: Use of these regimens are permitted with (1) anti angiogenic agents (such as bevacizumab) or (2) targeted therapy (such as anti epidermal growth factor receptor agents); * Subjects must have a local platelet count ≤ 85 x 10\^9/L on study day 1. * Subjects must be at least 14 days removed from the start of the chemotherapy cycle immediately prior to study day 1 if they received FOLFOX, FOLFIRINOX or FOLFOXIRI, and 21 days removed if they received CAPEOX. * Subjects must have at least 3 remaining planned cycles of chemotherapy at study enrollment. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Exclusion criteria
Previous or Current Medical Conditions * Acute lymphoblastic leukemia. * Acute myeloid leukemia. * Any myeloid malignancy. * Myelodysplastic syndrome. Baseline bone marrow biopsy is not required to rule out MDS. However, if a bone marrow biopsy and cytogenetics were performed as part of diagnostic or staging work-up, these results will be collected to confirm. * Myeloproliferative disease. * Multiple myeloma. * Within 4 months prior to enrollment, any history of active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, screening ECG with corrected QT (QTc) interval of \> 470 msec, pericardial disease, or myocardial infarction. * Major surgery ≤ 28 days or minor surgery ≤ 3 days prior to enrollment. * New or uncontrolled venous thromboembolism or thrombotic events within 3 months prior to screening. To be eligible, subjects must have received at least 14 days of anticoagulation for a new thrombotic event and considered to be both stable and suitable for continued therapeutic anticoagulation during trial participation. * History of arterial thrombosis (eg, stroke or transient ischemic attack) within 6 months of screening. * Evidence of active infection within 2 weeks prior to first dose of study treatment. * Known human immunodeficiency virus infection. Subjects without a documented diagnosis in their medical history will require a local laboratory assessment at screening. If local laboratory results are not available, use central laboratory results. * Known active chronic hepatitis B or C infection. Subjects without a documented diagnosis in their medical history will require a local laboratory assessment at screening. If local laboratory results are not available, use central laboratory results. Hepatitis B and C infection is based on the following results: * Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B). * Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B. * Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C. * Secondary malignancy within the past 5 years except: * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated cervical carcinoma in situ without evidence of disease. * Adequately treated breast ductal carcinoma in situ without evidence of disease. * Prostatic intraepithelial neoplasia without evidence of prostate cancer. * Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. * Malignancy treated with curative intent and with no known active disease present for at least 3 years before enrollment and felt to be at low risk for recurrence by the treating physician * Thrombocytopenia due to another etiology other than CIT (eg, chronic liver disease, prior history of immune thrombocytopenia purpura). Prior/Concomitant Therapy • Previous use of romiplostim, pegylated recombinant human megakaryocyte growth and development factor, eltrombopag, recombinant human TPO, any other TPO receptor agonist, or any investigational platelet producing agent. Prior/Concurrent Clinical Study Experience • Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. Diagnostic Assessments * Anemia (hemoglobin \<80 g/L \[8 g/dL\]) on the day of initiation of investigational product as assessed by local labs. Use of red cell transfusions and erythropoietic stimulating agents is permitted throughout the study as per institutional guidelines. * Neutropenia (absolute neutrophil count 1 x 10\^9/L) on the day of initiation of investigational product as assessed by local labs. Use of granulocyte-colony stimulating factor is permitted throughout the study as per institutional guidelines. * Abnormal renal function with creatinine clearance \< 30 mL/min using the Cockcroft-Gault estimated creatinine clearance as assessed by local laboratory during screening. If local laboratory results are not available, use central laboratory results. * Abnormal liver function (total bilirubin \> 3 X ULN; alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 3 X ULN for subjects without liver metastases or ≥ 5 X ULN for subjects with liver metastases) as assessed by local laboratory during screening. If local laboratory results are not available, use central laboratory results. Other Exclusions * Females who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after treatment (and chemotherapy) discontinuation (females of childbearing potential should only be included after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.) * Females of childbearing potential unwilling to use a highly effective method of contraception during treatment and for an additional 6 months after treatment (and chemotherapy) discontinuation. * Males unwilling to use contraception\* (male condom or sexual abstinence) or their female partner(s) of childbearing potential who are unwilling to use a highly effective method of contraception during treatment (and chemotherapy) and for an additional 6 months after treatment (and chemotherapy) discontinuation. \*If the male's sole partner is of non-childbearing potential, he is not required to use additional forms of contraception during the study. * Subject has known sensitivity to any of the products to be administered during dosing. * Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, COAs) to the best of the subject and investigator's knowledge. * History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. * Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment (and chemotherapy) and for an additional period of 6 months after treatment (and chemotherapy) discontinuation. * Male subjects unwilling to abstain from donating sperm during treatment (and chemotherapy) and for an additional 6 months after treatment (and chemotherapy) discontinuation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had Thrombocytopenia-induced Dose Modification | Day 1 up to Week 12 | Participants met the criteria of the primary endpoint if there was no thrombocytopenia-induced modification of any myelosuppressive treatment agent in the second and third cycles of the planned on-trial chemotherapy regimen (cycles were up to 3 weeks). A thrombocytopenia-induced modification was defined as any dose reduction, dose delay, dose omission, and/or early chemotherapy treatment discontinuation due to low platelet counts less than 100 x 10\^9/L. The 95% confidence interval (CI) is based on the exact Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Count Nadir at the End of the Treatment Period | Up to 21 weeks | The platelet count nadir from the first on-trial chemotherapy through the end of the treatment period is presented. The least squares (LS) mean platelet count nadirs were estimated using a general linear model which included treatment, stratification factors, and the interaction between treatment and the stratification factors (tumor type and baseline platelet count). |
| Kaplan-Meier Estimate of Time to First Platelet Response | Up to 21 weeks | Platelet response was defined as achieving a platelet count of ≥ 100 x 10\^9/L in the absence of platelet transfusions during the preceding 7 days. Participants who did not achieve a response event during the treatment period were censored at their last platelet count assessment up to end of treatment period or at the randomization date if they did not have any post-baseline platelet assessments. |
| Duration-adjusted Event Rate of Bleeding Events in the Treatment Period | Up to 21 weeks | The duration-adjusted adverse event (AE) incidence rate was the number of events per 100 subject-years from the trial day 1 until the date of last dose of investigational product + 30 days, or end of trial, whichever is earlier. It was calculated as: duration-adjusted event rate per 100 subject years (n/Subj-yr) x 100. The duration-adjusted event rate was assessed for Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade 2 bleeding events. CTCAE grading for AEs ranges from Grade 1 (mild) to Grade 5 (death related to AE). Grade 2 AEs were moderate. |
| Overall Survival | From Day 1 up to 1 year after last dose of investigational product (IP) (max 1869 days) | Overall survival was defined as the time calculated from trial Day 1 to death. Participants who did not died were censored. |
| Percentage of Participants Who Had Platelet Transfusions During the Treatment Period | Up to 21 weeks | Participants who had at least 1 platelet transfusion during the treatment period. |
| Percentage of Participants Who Achieved a Platelet Count ≥ 100 x 10^9/L | Day 1 to Week 4 | The number of participants who achieved a platelet count ≥ 100 x 10\^9/L at any time after trial Day 1 to Week 4 (7 days after the planned third dose of IP). If a platelet transfusion occurred during the 7 days preceding a platelet count, then that platelet count was not considered as achieving the endpoint even if it is ≥ 100 x 109/L. Participants who had no platelet counts during this period were considered as not achieving achieved a platelet count ≥ 100 x 109/L. For participants who never received IP, the participants are considered as not achieving a platelet count ≥ 100 x 109/L. Weeks with no platelet count measurements (missing data) were considered as not achieving a platelet count ≥ 100 x 109/L. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Fatal AEs | From first dose of IP to 30 days after last dose of IP: median (min, max) duration was 86.0 (31.0, 184.0) days | An AE was defined as any untoward medical occurrence in a clinical trial participant. A TEAE was an AE that started on or after the first dose of IP up to 30 days after the end of investigational product or last dose of on-trial chemotherapy (up to 3 cycles), whichever occurs later. Clinically significant changes in laboratory values were considered AEs. A SAE was defined as any untoward medical occurrence that, met at least 1 ofthe following criteria: resulted in death (fatal), immediately life-threatening,required in-patient hospitalization or prolongation of existing hospitalization,resulted in persistent or significant disability/incapacity or was a congenitalanomaly/birth defect. |
| Number of Participants Who Developed Anti-romiplostim Antibodies and Anti-thrombopoietin (TPO) Antibodies | Up to 21 weeks | Blood samples were collected from all participants for the measurement of anti-romiplostim and anti-TPO binding antibodies. Participants were tested for the presence of anti-romiplostim and anti-TPO antibodies at baseline (pre-existing antibody) and post-baseline (developed antibody). Samples testing positive for binding antibodies were also be tested for neutralizing antibodies. |
| Number of Participants Who Reported Myelodysplastic Syndromes (MDS) and SecondaryMalignancies | From Day 1 up to 1 year after last dose of IP (max 1869 days) | Events were identified using narrow search of pre-defined list of preferred terms for myelodysplastic syndromes (SMQ). Secondary malignancies included progression from myelodysplastic syndrome to acute myeloid leukemia (AML). |
Countries
Argentina, Austria, Brazil, Bulgaria, Canada, Colombia, France, Greece, Hungary, Italy, Mexico, Peru, Poland, Portugal, Romania, Russia, Spain, Turkey (Türkiye), Ukraine, United States
Contacts
STUDY_DIRECTORMD
Amgen
Participant flow
Recruitment details
Participants were enrolled in 55 trial centers in Bulgaria, Greece, Italy, Poland, Portugal, Romania, Spain, Argentina, Brazil, Canada, Mexico, Russia, Turkey, and the United States.
Pre-assignment details
Adult participants receiving oxaliplatin-based chemotherapy regimens for the treatment of gastrointestinal, pancreatic, or colorectal adenocarcinoma were enrolled. Participants were randomized in a 2:1 ratio to receive either romiplostim or placebo, respectively. Randomization was stratified by tumor type and baseline platelet count (\<50 x 10\^9/L and ≥ 50 x 10\^9/L).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 75 Participants |
| Age, Categorical Between 18 and 65 years | 90 Participants |
| Age, Continuous | 61.6 years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Mean Baseline Platelet Count | 66.027 10^9 platelets per L STANDARD_DEVIATION 14.062 |
| Race/Ethnicity, Customized Black (or African American) | 4 Participants |
| Race/Ethnicity, Customized Other | 11 Participants |
| Race/Ethnicity, Customized White | 148 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 25 / 55 | 58 / 110 |
| other Total, other adverse events | 28 / 55 | 76 / 110 |
| serious Total, serious adverse events | 3 / 55 | 23 / 110 |
Outcome results
None listed