Study of Romiplostim for Chemotherapy-induced Thrombocytopenia in Adult Subjects With Non-small Cell Lung Cancer (NSCLC), Ovarian Cancer, or Breast Cancer

Study Overview
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Brief Summary
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To evaluate the efficacy of romiplostim for the treatment of CIT in patients receiving chemotherapy for the treatment of NSCLC, ovarian cancer, or breast cancer measured by the ability to administer on-time, full-dose chemotherapy

Detailed Description
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This is a phase 3, randomized, placebo-controlled, multicenter, international study for the treatment of CIT in adult subjects receiving chemotherapy for the treatment of NSCLC, ovarian cancer, or breast cancer. Subjects must have a platelet count ≤ 85 x 10^9/L on day 1 of the study. The study will consist of a screening period of up to 4 weeks, a treatment period long enough to allow for assessment of 3 planned cycles of chemotherapy, a follow-up visit, and long-term follow-up (LTFU). Given that subjects are required to have 3 remaining planned cycles of chemotherapy, the chemotherapy cycles may be 3 or 4 weeks in duration, and the investigational product dose adjustment guidelines allow for up to 12 weeks of dosing before a subject is declared a non-responder, the majority of study subjects will receive investigational product for a range of 10-24 weeks.

Official Title
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PROCLAIM: A Phase 3 Randomized Placebo-controlled Double-blind Study of Romiplostim for the Treatment of Chemotherapy-induced Thrombocytopenia in Patients Receiving Chemotherapy for Treatment of Non-small Cell Lung Cancer (NSCLC), Ovarian Cancer, or Breast Cancer

Conditions
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Chemotherapy-induced Thrombocytopenia

Intervention / Treatment
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* Drug: Romiplostim
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. Documented active stage I, II, III or IV locally advanced or metastatic of the following tumor types: NSCLC, breast cancer, or ovarian cancer (includes fallopian tube epithelial carcinomas and peritoneal epithelial carcinoma of unknown primary), or any stage recurrent disease. Patients with documented locally advanced (stage III) NSCLC should not be amenable to definitive treatment with chemoradiation and/or surgery. Subjects must be receiving cancer treatment with 21- or 28-day cycles, using one of the following carboplatinum-based combination chemotherapy regimens: carboplatin/gemcitabine based, carboplatin/pemetrexed based, carboplatin/liposomal doxorubicin based or carboplatin/taxane based (which includes either paclitaxel, nab-paclitaxel, or docetaxel) or single agent chemotherapy regimen with any of the above mentioned drugs. Use of combination regimens with one of the above carboplatinum-based regimens is permitted with (1) anti-angiogenic agents (such as bevacizumab); (2) targeted therapy (such as anti-epidermal growth factor agents or anti- human epidermal growth factor receptor 2) or (3) immune checkpoint inhibitors. Cycle duration is based on intervals between day 1 of chemotherapy cycles (overlapping with carboplatin intervals) every 21 or 28 day cycles for single agent regimens. OR, Subjects must have CIT from a non-protocol chemotherapy regimen, planning to start treatment with one of the above protocol chemotherapy regimens which has been delayed ≥ 1 week due to CIT. Subjects must have a local platelet count ≤ 85 x 109/L on day 1 of the study. Subjects must be at least 21 or 28 days removed from the start of the chemotherapy cycle immediately prior to study day 1 if receiving a 21-day or 28-day cycle chemotherapy regimen, respectively. 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: 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 greater than 470 msec, pericardial disease, or myocardial infarction. Major surgery less than or equal to 28 days or minor surgery less than or equal to 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 stable and suitable for continued therapeutic anticoagulation during trial participation. History of arterial thrombotic events (eg, myocardial ischemia, transient ischemic attack, or stroke) within 6 months prior to screening. Evidence of active infection within 2 weeks prior to the first dose of study treatment. Known human immunodeficiency virus infection with any detectable viral load at screening. 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 of chronic hepatitis C or hepatitis B 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: hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C. In addition to the conditions listed in exclusion criteria 201 through 206, 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 greater than or equal to 3 years before enrollment and felt to be at low risk for recurrence by the treating physician (excluding malignancies listed in exclusion criteria 201 - 206). Thrombocytopenia due to another etiology other than CIT (eg, chronic liver disease, prior history of immune thrombocytopenia purpura). Any combined modality regimen containing radiation therapy or surgery occurring concomitantly with neo-adjuvant chemotherapy or where radiation therapy is planned during the cycle preceding 3 planned on-study cycles of chemotherapy. 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 (or plan to receive) 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 less than 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 less than 30 mL/min using the Cockcroft-Gault estimated creatinine clearance as assessed by local laboratory. If local laboratory results are not available use central laboratory results. during screening. - Abnormal liver function (total bilirubin greater than 3X ULN; alanine aminotransferase [ALT] or aspartate aminotransferase [AST] greater than 3X ULN for subjects without liver metastases or greater than or equal to 5X 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 7 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 7 months after treatment (and chemotherapy) discontinuation. Refer to Appendix 5 for additional contraceptive information. 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 7 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 7 months after treatment (and chemotherapy) discontinuation. Male subjects unwilling to abstain from donating sperm during treatment (and chemotherapy) and for an additional 7 months after treatment (and chemotherapy) discontinuation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will consist of a screening period of up to 4 weeks, a treatment period long enough to allow for assessment of 3 planned cycles of chemotherapy, a follow-up visit, and LTFU. Given that subjects are required to have 3 remaining planned cycles of chemotherapy, the chemotherapy cycles may be 3 or 4 weeks in duration, and the investigational product dose adjustment guidelines allow for up to 12 weeks of dosing before a subject is declared a non-responder, the majority of study subjects will receive investigational product for a range of 10-24 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Romiplostim<br>The study in a 2:1 randomization ratio(108 subjects to romiplostim). Amgen investigational product (romiplostim or placebo) will be administered in the clinic by a qualified healthcare provider as a subcutaneous injection. | Drug: Romiplostim<br>* This study is designed to study Romiplostim for the treatment of chemotherapy-induced thrombocytopenia (CIT) in patients receiving chemotherapy for the treatment of non-small cell lung cancer (NSCLC), ovarian cancer, or breast cancer<br>* Other names: Nplate;|
| Placebo Comparator: Placebo<br>The study in a 2:1 randomization ratio (54 subjects to placebo) Amgen investigational product (romiplostim or placebo) will be administered in the clinic by a qualified healthcare provider as a subcutaneous injection. | Drug: Placebo<br>* Placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of either a chemotherapy dose delay or reduction | No thrombocytopenia-induced modification of any myelosuppressive 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 | 48 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depth of Platelet Count | the depth of the platelet count nadir from the start of the first on-study chemotherapy cycle through the end of the treatment period | 48 days | 
| Time to First platelet response | 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 | 7 days | 
| the duration-adjusted event rate of ≥ grade 2 bleeding events | 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 | 48 days | 
| Overall survival | 1-year overall survival | 1 Year | 
| Proportion of subjects with at leat 1 incidence of platelet transfusion | platelet transfusion(s) during the treatment period | 48 days | 
| proportion of patients achieving platelet count >= 100 x 10 9/L | 7 days after 3rd dose of IP with no transfusions in preceding 7 days | 7 days | 
| The subject incidence of adverse events | Through end of study, up to 36 months. It will be counted in as an adverse event: any treatment - emergent adverse events, fatal adverse events, serious adverse events, or clinically significant changes in laboratory values. | 36 months | 
| Number of subjects who develop anti-romiplostim antibodies | Through end of study up to 36 months | 36 Months | 
| Number of subjects who develop anti-TPO antibodies | Through end of study, up to 36 months | 36 months | 
| Number of subjects who experience myelodysplastic syndromes | Through end of study, up to 36 months | 36 months | 
| Number of subjects who experience secondary malignancies | Through end of study, up to 36 months | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemotherapy-induced thrombocytopenia, Non-small Cell Lung Cancer, Ovarian Cancer, Breast Cancer