E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
gastrointestinal or colorectal adenocarcinoma, which includes cancers of the esophagus, stomach, colon, or rectum. |
|
E.1.1.1 | Medical condition in easily understood language |
cancers of the esophagus, stomach, colon, or rectum |
|
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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052360 |
E.1.2 | Term | Colorectal adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053548 |
E.1.2 | Term | Gastrointestinal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 romiplostim for the treatment of chemotherapy-induced thrombocytopenia (CIT) in patients receiving chemotherapy for the treatment of gastrointestinal or colorectal cancer, measured by the ability to administer on-time, full-dose chemotherapy |
|
E.2.2 | Secondary objectives of the trial |
- to compare the treatment effect of romiplostim with that of placebo on the depth of platelet nadir
- to compare the treatment effect of romiplostim with that of placebo on the time to first platelet response
- to compare the treatment effect of romiplostim with that of placebo on the incidence of ≥ grade 2 bleeding events
-to compare the treatment effect of romiplostim with that of placebo on overall survival
- to compare the treatment effect of romiplostim with that of placebo on the incidence of platelet transfusions
-to compare the treatment effect of romiplostim with that of placebo on the proportion of patients achieving platelet response
-overall safety of romiplostim |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 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.
2. Males or females ≥ 18 years of age at signing of the informed consent.
3. Histologically or cytologically confirmed diagnosis of gastrointestinal or colorectal adenocarcinoma, defined as cancers of the esophagus, stomach, colon, or rectum. Tumor stage will not affect eligibility.
4. Subjects must be receiving a FOLFOX-based chemotherapy regimen, containing 5-FU and oxaliplatin, on a 14-day schedule.
Note: Use of a FOLFOX-based combination regimen is permitted with (1)
anti-angiogenic agents (such as bevacizumab) or (2) targeted therapy (such as anti-epidermal growth factor receptor agents). FOLFOXIRI-based regimens will not be allowed.
5. Subjects must have a platelet count < 75 x 109/L on study day 1.
6. Subjects must be at least 14 days removed from the start of the chemotherapy cycle immediately prior to study day 1.
7. Subjects must have at least 3 remaining planned cycles of chemotherapy at study enrollment.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. |
|
E.4 | Principal exclusion criteria |
1.Acute lymphoblastic leukemia.
2.Acute myeloid leukemia.
3.Any myeloid malignancy.
4.Myelodysplastic syndrome.
5.Myeloproliferative disease.
6.Multiple myeloma.
7.Within 4 months prior to enrollment, any history of active congestive heart failure
8.Major surgery ≤ 28 days or minor surgery ≤ 3 days prior to enrollment.
9.New or uncontrolled venous thromboembolism or thrombotic events within 3 months prior to screening.
10.History of arterial thrombosis (eg, stroke or transient ischemic attack) within 6 months of screening.
11.Evidence of active infection within 2 weeks prior to first dose of study treatment.
12.Known human immunodeficiency virus infection.
13.Known active chronic hepatitis B or C infection.
14.In addition to the conditions listed in exclusion criteria 1 through 6,
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 ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician (excluding malignancies listed in exclusion criteria 1 – 6).
15.Thrombocytopenia due to another etiology other than CIT (eg, chronic liver disease, prior history of immune thrombocytopenia purpura).
Prior/Concomitant Therapy
16.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
17.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
18.Anemia (hemoglobin < 8 g/dL)
19.Neutropenia (absolute neutrophil count < 1 x 109/L)
20.Abnormal renal function with creatinine clearance < 30 mL/min using the Cockcroft-Gault estimated creatinine clearance
21.Abnormal liver function (total bilirubin > 3X ULN; alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3X ULN for subjects without liver metastases or ≥ 5X ULN for subjects with liver metastases)
Other Exclusions
22.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 pregnancy test)
23. 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.
24. 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.
25. Subject has known sensitivity to any of the products to be administered during dosing.
26.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.
27.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.
28. 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.
29. Male subjects unwilling to abstain from donating sperm during treatment (and chemotherapy) and for an additional 6 months after treatment (and chemotherapy) discontinuation.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
no thrombocytopenia-induced modification of any myelosuppressive treatment agent in the second and third cycles of the planned on-study chemotherapy regimen. Thrombocytopenia-induced modifications include chemotherapy dose reduction, delay, omission, or chemotherapy treatment
discontinuation due to platelet counts below 100 x 109/L |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be performed at the primary completion date. The primary completion date is defined as the date when the last subject is assessed or receives an intervention for the final collection of data for the primary endpoint. |
|
E.5.2 | Secondary end point(s) |
• the depth of the platelet count nadir from the start of the first on-study chemotherapy cycle through the end of the treatment period
• the time to first platelet response, defined by platelet count ≥ 100 x 109/L in the absence of platelet transfusions during the preceding 7 days
• the duration-adjusted event rate of ≥ grade 2 bleeding events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
grading scale
• overall survival
• platelet transfusion(s) during the treatment period
• achieving a platelet count ≥ 100 x 109/L at any time after study day 1 to week 4 (ie, 7 days after the planned third dose of investigational product) and in the absence of platelet transfusions during the preceding 7 days
• adverse events, including treatment-emergent adverse events, fatal adverse events, serious adverse events, and clinically significant changes in
laboratory values.
• anti-romiplostim antibodies and antibodies to thrombopoietin (TPO)
• myelodysplastic syndromes and secondary malignancies |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The primary analysis will be performed at the primary completion date. The primary completion date is defined as the date when the last subject is assessed or receives an intervention for the final collection of data for the primary endpoint.
-When the last subject in the trial completes LTFU at 1 year after the last dose of investigational product, the final database will be locked for the final analysis. In the final analysis, the secondary endpoints assessment, and all the exploratory endpoints will be evaluated |
|
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 | No |
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 | No |
E.8.1.6 | Cross over | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
Argentina |
Austria |
Brazil |
Bulgaria |
Canada |
Chile |
Colombia |
France |
Greece |
Hungary |
Italy |
Mexico |
Peru |
Poland |
Portugal |
Romania |
Russian Federation |
Spain |
Ukraine |
United States |
|
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
|
The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (i.e. last subject last visit), following any additional parts in the study (eg, LTFU), as applicable. Based on the definition above, the EOS date is the date when the last subject in the trial has completed his/her EOS visit |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 22 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |