Clinical Trials /

Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With r/r Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

NCT03571828

Description:

Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL, or FL. Estimate the maximum tolerated dose (MTD) and/or a biologically active dose (e.g., recommended phase 2 dose [RP2D])

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Double-Hit Lymphoma
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With r/r Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma
  • Official Title: A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With Relapsed / Refractory Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 20170533
  • NCT ID: NCT03571828

Conditions

  • Diffuse Large B-cell Lymphoma(DLBCL)
  • Mantle Cell Lymphoma (MCL)
  • Follicular Lymphoma (FL)

Interventions

DrugSynonymsArms
AMG 562Part 1: Dose Exploration

Purpose

Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL, or FL. Estimate the maximum tolerated dose (MTD) and/or a biologically active dose (e.g., recommended phase 2 dose [RP2D])

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose ExplorationExperimentalDose exploration cohorts to estimate the MTD, safety, tolerability, and PK of different doses of AMG 562 in subjects with relapsed/refractory DLBCL, MCL or FL using a Bayesian logistic regression model (BLRM; Neuenschwander et al, 2008).
  • AMG 562
Part 2: Dose ExpansionExperimentaldose expansion part to gain further clinical experience, safety and efficacy data for AMG 562 in subjects with relapsed / refractory DLBCL. The dose to be evaluated will be at or below the MTD estimated in the dose exploration cohorts.
  • AMG 562

Eligibility Criteria

        Inclusion Criteria:

          -  Subject has provided informed consent prior to initiation of any study-specific
             activities/procedures

          -  Age ≥ 18 at the time of informed consent.

          -  Biopsy proven B-NHL including:

               -  DLBCL, which also includes DLBCL that represents transformation of indolent NHL
                  (including follicular, marginal zone, and lymphoplasmacytic lymphoma excluding
                  chronic lymphocytic leukemia or Hodgkin Lymphoma) and DLBCL with alterations of
                  MYC and BCL2 and/or BCL6 also described as double-hit and triple-hit lymphomas.

               -  FL

               -  MCL Presentations of these histologies with substantial occurrence of malignant
                  cells into the bloodstream (lymphocyte count ≥ 7 x 10^9/L) including all leukemic
                  presentations are excluded.

        The following histologies are not eligible:

        Lymphoblastic lymphoma Burkitt lymphoma Any histologies not specifically mentioned must be
        discussed with the Medical Monitor

          -  Subjects with transformation of indolent lymphoma must have received therapy after a
             diagnosis of transformation that is appropriate for aggressive histology.

             - Subjects who received prior CD19-targeting treatment are allowed (CAR-T cell therapy
             is excluded). A biopsy following CD19-targeting treatment is required unless no
             lesions are accessible or the risk of the biopsy is deemed too high by the
             investigator For Part 2 (Expansion in patients with DLBCL): only biopsy proven DLBCL
             (biopsy proven at least at primary diagnosis), including DLBCL that represents
             transformation of indolent NHL (including follicular, marginal zone, and
             lymphoplasmacytic lymphoma excluding chronic lymphocytic leukemia or Hodgkin Lymphoma)
             are eligible. Other histologies are not eligible.

          -  Presentations of these histologies with substantial occurrence of malignant cells into
             the bloodstream (lymphocyte count ≥ 7 x 10^9/L) including all leukemic presentations
             are excluded.

          -  Subjects with transformation of indolent lymphoma must have received therapy after a
             diagnosis of transformation that is appropriate for aggressive histology as described
             in inclusion criterial.

          -  Subjects who received prior CD19-targeting treatment are allowed (CAR-T cell therapy
             is excluded) A biopsy following CD19-targeting treatment is required unless no lesions
             are accessible or the risk of the biopsy is deemed too high by the investigator - For
             DLBCL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed
             (prior CR/CMR) after two or more prior treatments, with at least one treatment
             consisting of standard multiagent chemotherapy containing an anthracycline AND an
             approved anti-CD20 agent. Examples of appropriate therapy include but are not limited
             to R-CHOP (14 or 21), R-CHOEP, and DA-R-EOCH.

        For FL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed (prior
        CR/CMR) after three or more prior treatments, with at least one treatment consisting of a
        standard chemotherapy containing an approved anti-CD20 agent.

        Examples of appropriate therapy include but are not limited to R-CHOP, R-CVP, and BR.

        For MCL: Refractory (no prior CR/CMR) to first or later line of treatment or relapsed
        (prior CR/CMR) after three or more prior treatments, with at least one treatment consisting
        of a standard chemotherapy containing an approved anti-CD20 agent. Examples of appropriate
        therapy include but are not limited to R-CHOP, BR and hyper-CVAD alternating with
        R-MTX/Ara-C.

        For subjects with refractory B-NHL and who have received radiotherapy, PET positivity
        should be demonstrated no less than 6 weeks after the last dose of radiotherapy

          -  Minimum life expectancy of 12 weeks

          -  Radiographically measurable disease with a clearly demarcated nodal lesion at least
             1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in its
             largest dimension. In the dose exploration phase in case disease is not
             radiographically measurable PET positivity (ie, Deauville ≥4) instead is acceptable.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Laboratory parameters (completed within 14 days prior to enrollment):

        Hematology:

          -  Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L

          -  Platelets ≥ 75 x 10^9/L

        Chemistry:

          -  Creatinine clearance ≥ 60 mL/min (calculated using Cockcroft Gault equation)

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3X upper limit of
             normal (ULN)

          -  Total bilirubin (TBL) < 2x ULN (unless Gilbert's disease or if liver involvementwith
             lymphoma)

        Exclusion Criteria:

          -  Treatment within 30 days prior to enrollment with another investigational device or
             drug (interventional clinical study / studies). Other investigational procedures while
             participating in this study are excluded (observational studies are permitted).

          -  Prior anti-cancer therapy as specified below:

               -  At least 6 weeks must have elapsed since any prior systemic
                  inhibitory/stimulatory immune checkpoint molecule therapy (eg, ipilimumab,
                  nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc)
                  before the first dose of AMG 562.

               -  Other targeted anti-cancer therapy (chemotherapy, molecular targeted therapy,
                  steroids) within 14 days or 5 half lives (which ever is longer) prior to first
                  dose of AMG 562. Patients requiring continued treatment due to aggressive disease
                  may only be included if there is agreement by both the investigator and the Amgen
                  Medical Monitor.

               -  Radiation therapy completed within 28 days prior to first dose of AMG 562.

               -  Autologous HSCT within six weeks prior to start of AMG 562 treatment.

               -  At least 4 weeks must have elapsed since any prior treatment with antibody
                  therapy (exception immune checkpoint inhibitors) before the first dose of AMG
                  562.

          -  Prior CD19-directed CAR-T cell therapies

          -  Prior allogeneic HSCT.

          -  For Part 2 (Expansion in patients with DLBCL): fluorodeoxyglucose non-avid patients.

          -  Baseline electrocardiogram (ECG) QTc > 470 msec.

          -  Autoimmune disorders requiring chronic systemic steroid therapy or any other form of
             immunosuppressive therapy. Patient may be included if the treatment is discontinued
             more than 3 months prior to the first dose of AMG 562 at a low likelihood of relapse
             AND if there is agreement by both the investigator and the Amgen Medical Monitor.

          -  Unresolved toxicity from prior anti-tumor therapy, defined as not having resolved to
             CTCAE version 4.0 grade 1, or to levels dictated in the eligibility criteria with the
             exception of alopecia or toxicities from prior anti-tumor therapy that are considered
             irreversible (defined as having been present and stable for > 28 days) which may be
             allowed if they are not otherwise described in the exclusion criteria AND there is
             agreement to allow by both the investigator and the Amgen Medical Monitor.

          -  Presence of clinically relevant central nervous system (CNS) pathology such as
             epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's
             disease, cerebellar disease, organic brain syndrome, or psychosis.

          -  Evidence of CNS involvement by NHL.

          -  Known infection with human immunodeficiency virus (HIV).

          -  Exclusion of hepatitis infection based on the following results and/or criteria:

               -  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: Assay for 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): Assay for hepatitis C virus RNA by
                  PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C.

          -  History of malignancy other than B-NHL within the past 3 years with the exception of:

               -  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.

               -  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.

          -  Major surgery within 28 days of first dose AMG 562.

          -  History of arterial thrombosis (eg, stroke or transient ischemic attack) within 12
             months of first dose of AMG 562.

          -  Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials
             for management within 7 days of first dose AMG 562. NOTE: Simple UTI and uncomplicated
             bacterial pharyngitis are permitted after consultation with sponsor and if responding
             to active treatment.

          -  Subject has known sensitivity to immunoglobulins or any of the products or components
             to be administered during dosing.

          -  Males and females of reproductive potential who are unwilling to practice highly
             effective method(s) of birth control while on study through 110 days (females) and 170
             days (males) after receiving the last dose of study drug. Highly effective methods of
             birth control include sexual abstinence (males, females); vasectomy; bilateral tubal
             ligation/occlusion; or a condom with spermicide (males) in combination with hormonal
             birth control or intrauterine device (IUD) (females).

          -  Females who are lactating/breastfeeding or who plan to breastfeed while on study
             through 110 days after receiving the last dose of study drug.

          -  Females with a positive pregnancy test.

          -  Females planning to become pregnant while on study through 110 days after receiving
             the last dose of study drug.

          -  Males who are unwilling to abstain from sperm donation while on study through 170 days
             after receiving the last dose of study drug.

          -  Subjects likely to not be available to complete all protocol- required study visits or
             procedures including BM aspirates/biopsies, and/or to comply with all required study
             procedures to the best of the subject and investigator's knowledge.

          -  History or evidence of any other clinically-relevant concurrent disorder, condition or
             disease (eg, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia requiring therapy at time of screening) with the exception of those
             outlined above that, in the opinion of the investigator or Amgen medical monitor, if
             consulted, would not pose a risk to subject safety or interfere with the study
             evaluation, procedures or completion.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities (DLTs)
Time Frame:up to 2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Maximum observed concentration (Cmax) of AMG 562
Time Frame:Day 1, 8, 15, 22
Safety Issue:
Description:
Measure:minimum concentration (Cmin)
Time Frame:Day 1, 8, 15, 22
Safety Issue:
Description:
Measure:time of maximum concentration (Tmax)
Time Frame:Day 1, 8, 15, 22
Safety Issue:
Description:
Measure:area under the concentration-time curve (AUC)
Time Frame:Day 1, 8, 15, 22
Safety Issue:
Description:
Measure:Half Life (t1/2)
Time Frame:Day 1, 8, 15, 22
Safety Issue:
Description:
Measure:Efficacy-Overall Response
Time Frame:Week 5, 15, 20, 25 and EoT
Safety Issue:
Description:
Measure:Efficacy-Objective Response Rate (ORR)
Time Frame:Week 5, 15, 20, 25 and EoT
Safety Issue:
Description:
Measure:Efficacy-Duration of Response (DOR)
Time Frame:Week 5, 15, 20, 25 and EoT
Safety Issue:
Description:
Measure:Efficacy-Progression Free Survival (PFS)
Time Frame:Week 5, 15, 20, 25 and EoT
Safety Issue:
Description:
Measure:Efficacy-Overall Survival (OS)
Time Frame:Week 5, 15, 20, 25 and EoT
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Amgen

Last Updated

October 28, 2019