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

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

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

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

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.

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.

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.

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.

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

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

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

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.

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.

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.