Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies

Study Overview
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Brief Summary
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Evaluate the safety and tolerability of AMG 397. Estimate the maximum tolerated doses (MTDs) and/or biologically active doses.

Detailed Description
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This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating AMG 397 administered orally once weekly, as part of a 28-day treatment cycle in adult subjects with selected relapsed or refractory hematological malignancies

Official Title
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A Phase 1 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 397 in Subjects With Selected Relapsed or Refractory Hematological Malignancies

Conditions
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Multiple Myeloma, Acute Myeloid Leukemia, Non-Hodgkins Lymphoma, Myelodysplastic Syndrome, AML, MDS, NHL

Intervention / Treatment
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* Drug: AMG 397
* Drug: Dexamethasone
* Drug: Azacitidine


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 Age ≥ 18 years old Pathologically-documented, definitively-diagnosed relapsed or refractory multiple myeloma (MM), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) and is intolerant to, or considered ineligible for available therapies known to provide clinical benefit MM subjects only: Measurable disease per the International Myeloma Working Group (IMWG) response criteria (assessed within 21 days prior to enrollment), as indicated by one or more of the following: cytogenic risk factor: 1q21 amplification/gain, serum M-protein ≥ 0.5 g/dL, Urine M-protein ≥ 200 mg/24 hours. For Subjects who do not meet 1 of the 2 prior criteria: Serum Free Light Chain (sFLC) ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal sFLC ratio (< 0.26 or > 1.65) as per the IMWG response criteria MM subjects only: Hematological function, as follows without transfusion or growth factor support within 2 weeks prior to study day 1: absolute neutrophil count ≥ 1.0 X 109/L, hemoglobin > 8 g/dL and platelet count ≥ 75 X 109/L AML subjects only: Pathologically confirmed diagnosis of AML as defined by the World Health Organisation (WHO) Classification, more than 5% blasts in bone marrow and persisting or recurring following one or more treatment courses MDS subjects only: pathologically confirmed diagnosis of MDS as defined by the WHO Classification, intermediate and high risk MDS and intolerant or refractory to HMA treatment Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 Life expectancy of > 3 months, based on the opinion of the investigator Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption. Hepatic function, as follows: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) total bilirubin (TBL) < 1.5 X ULN (except subjects with Gilbert's syndrome) Cardiac function, as follows: Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion as determined by echocardiogram or multigated acquisition (MUGA) scan no ECG findings representing a recent cardiac injury within 6 months before enrollment Renal function as follows: Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault [(140 - Age) × Mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female Exclusion Criteria: Disease Related Previously received an allogeneic stem cell transplant within 6 months of study day 1 OR having signs or symptoms of acute or chronic graft-versus-host disease Autologous stem cell transplant < 90 days before enrollment Candidates for stem cell transplant should have failed or are not considered eligible for either allogeneic and autologous transplant Other Medical Conditions History of other malignancy except: Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician 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 Myocardial infarction within 6 months before enrollment Symptomatic congestive heart failure (New York Heart Association > Class II) History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 months before enrollment Uncontrollable active infection requiring intravenous anti-infective treatments within 1 week before enrollment Known positive results for human immunodeficiency virus (HIV) Active hepatitis B and C 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 Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1, or to levels dictated in the eligibility criteria with the exception of grade 2peripheral neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 4 weeks prior to study day 1 may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor) Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, retinoid therapy, or investigational agent or procedures) within 14 days of day 1 Prior systemic radiation therapy must have been completed at least 28 days before study day 1. Prior focal radiotherapy completed at 14 days before study day 1 Females of reproductive potential who are unwilling to practice acceptable methods of highly effective contraception while on study through 8 months after receiving the last dose of study drug. Males who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with or without spermicide while on study through 5 months after receiving the last dose of study drug if sexually active with a female of childbearing potential Females who are lactating/breastfeeding or who plan to breastfeed while on study through 8 months after receiving the last dose of study drug Females with a positive pregnancy test or planning to become pregnant while on study through 8 months after receiving the last dose of study drug Males who are unwilling to abstain from sperm donation while on study through 8 months after receiving the last dose of study drug History or evidence of any other clinically significant disorder, condition or disease 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 Use of any over-the-counter or prescription medications within 14 days or 5 half-lives (whichever is longer), prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor Use of herbal medicines (eg, St. John's wort), vitamins, and supplements consumed by the subject within 14 days prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor Use of any known inhibitors of P-gp within 14 days or 5 half-lives (whichever is longer) or grapefruit juice or grapefruit containing products within 7 days prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor Use of known CYP3A4 sensitive substrates, (with a narrow therapeutic window), within 14 days or 5 half-lives (whichever is longer) of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor Use of known P-gp substrates (with a narrow therapeutic window) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not reviewed and approved by the principal investigator and the Amgen medical monitor 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, long term follow-up) to the best of the subject and investigator's knowledge Known sensitivity to any of the products or component to be administered during dosing MM subjects with any of the following criteria are excluded: Multiple myeloma with IgM subtype POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Existing plasma cell leukemia Waldenstrom's macroglobulinemia Amyloidosis AML subjects with the following criteria are excluded: Circulating white blood cells > 25,000/μl. Hydroxyurea to control peripheral blood leukemic cell counts, within 24 hours of study day 1 is permitted Promyelocytic leukemia AML/MDS subjects fit for intensive salvage therapy Subjects with elevated cardiac troponin above the manufacturer's 99th percentile upper reference limit for ADVIA Centaur XP assay at screening performed by the central laboratory (Covance) Subjects with evidence of recent cardiac injury at screening based on creatine kinase-muscle/brain (CK-MB), N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), and ECG assessments at screening Subjects with MDS that are eligible for hematopoietic stem cell transplant (HSCT)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A: AMG 397 Dose Escalation<br>This arm includes subjects with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL). | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>|
| Experimental: Part 1B: AMG 397 Dose Escalation<br>This arm includes subjects with acute myeloid leukemia (AML). | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>|
| Experimental: Part 2A: AMG 397 Monotherapy<br>This arm includes subjects with AML or myelodysplastic syndrome (MDS). | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>|
| Experimental: Part 2B: AMG 397 Monotherapy<br>This arm includes subjects with AML in Japan only. | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>|
| Experimental: Part 2C: AMG 397 Monotherapy<br>This arm includes subjects with MM. | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>|
| Experimental: Part 3A: AMG 397 + Azacitidine Combotherapy<br>This arm includes subjects MDS. | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>Drug: Azacitidine<br>* Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.<br>|
| Experimental: Part 3B: AMG 397+ Azacitidine Combotherapy<br>This arm includes subjects AML. | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>Drug: Azacitidine<br>* Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.<br>|
| Experimental: Part 3C: AMG 397+ Dexamethasone Combotherapy<br>This arm includes subjects MM. | Drug: AMG 397<br>* AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered intravenously (IV) or orally on Days 1, 8, 15, and 22 of each 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | DLTs were defined as specific adverse events (AEs) that occurred in a participant during the DLT evaluation period (Day 1 to Day 28), that the investigator assessed as related to AMG 397. The grading and severity of AEs were based on the guidelines provided in the common terminology criteria for adverse events (CTCAE) version 4.03. | 28 days | 
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | A TEAE was defined as any AE starting on or after the first dose of investigational product. Any clinically significant changes in vital signs, physical examinations, electrocardiogram (ECGs) and clinical laboratory test results were recorded as AEs. The grading and severity of adverse events were based on the guidelines provided in the CTCAE version 4.03. Treatment-related TEAEs were any events that the investigator assessed as related to AMG 397. | Up to 30 days after last dose (Maximum time on treatment was 18 weeks for part 1a and 13 weeks for part 1b) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM) | ORR was assessed for participants with MM using response criteria per International Myeloma Working Group (IMWG). ORR was defined as the percentage of participants who experienced either one of the following based on investigator assessment: partial response (PR) very good partial response (VGPR) complete response (CR) stringent complete response (sCR) | Up to end of study (a maximum of 48 weeks) | 
| Overall Response Rate (ORR) for Participants With Non-Hodgkin's Lymphoma (NHL) | ORR was assessed for participants with NHL using response criteria per Lugano Classification. ORR was defined as the percentage of participants who experienced either of the following based on investigator assessment: partial metabolic response/ PR complete metabolic response/ CR | Up to end of study (a maximum of 48 weeks) | 
| Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML) | ORR was assessed for participants with AML using response criteria per European Leukemia Network Response Criteria. ORR was defined as the percentage of participants who experienced either of the following based on investigator assessment: PR morphological leukemia-free state (MLFS) complete remission with incomplete hematologic recovery (CRi) complete remission complete remission without minimal residual disease (CRmrd-). | Up to end of study (a maximum of 48 weeks) | 
| Progression-free Survival (PFS) | PFS was calculated as time from first dose of investigational product date to disease progression date or death due to any cause, whichever was earlier. PFS time in months: (date of disease progression or death - first dose date +1)/30.4. | Up to end of study (a maximum of 48 weeks) | 
| Overall Survival (OS) | OS was defined as the time from first dose of investigational product date until death due to any cause. OS time in months: (date of death - first dose date +1)/30.4. | Up to end of study (a maximum of 48 weeks) | 
| Time to Response (TTR) | TTR was defined as the time from the first dose of investigational product until the first documentation of objective response. Only participants who achieved an objective response were evaluated for TTR. TTR time in months: (date of the first observation of response - first dose of IP date +1)/30.4. | Up to end of study (a maximum of 48 weeks) | 
| Duration of Response (DOR) | DOR was only planned to be calculated for participants who achieved response (PR or better). DOR was defined as time from the first observation indicating a response to the subsequent date of disease progression or death, whichever was earlier. DOR time in months: (date of disease progression or death - date of the first observation of response +1)/30.4. | Up to end of study (a maximum of 48 weeks) | 
| Maximum Observed Concentration (Cmax) of AMG 397 | Predose data for Day 2 were analyzed/included with the Day 1 data. | Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2 | 
| Time to Maximum Observed Concentration (Tmax) for AMG 397 | Predose data for Day 2 were analyzed/included with the Day 1 data. | Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2 | 
| Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 |  | Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22 | 
| Clearance (CL) of AMG 397 |  | Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22 | 
| Half-life (t1/2) of AMG 397 |  | Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, AML, MDS, MM, Myeloid Cell Leukemia 1 Inhibitor, MCL1 Inhibitor, MCL1