Clinical Trials /

Testing the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma

NCT03031730

Description:

This phase I trial studies the side effects and best dose of MDM2 Inhibitor KRT-232 when given together with carfilzomib, lenalidomide, and dexamethasone in treating patient with multiple myeloma that has come back (relapsed) or has not responded to previous treatment (refractory). KRT-232 (AMG 232) may stop the growth of cancer cells by blocking a protein called MDM2 that is needed for cell growth. Lenalidomide help shrink or slow the growth of multiple myeloma. Drugs used in chemotherapy, such as carfilzomib and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving MDM2 Inhibitor KRT-232, lenalidomide, carfilzomib, and dexamethasone together may work better in treating patients with multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MDM2 Inhibitor AMG-232, Carfilzomib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma
  • Official Title: A Phase 1 Dose-Escalation and Exploratory Dose Expansion Study of AMG 232 in Combination With Carfilzomib, Lenalidomide, and Dexamethasone in Relapsed and/or Refractory Myeloma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00099
  • SECONDARY ID: NCI-2017-00099
  • SECONDARY ID: NCI10076
  • SECONDARY ID: 10076
  • SECONDARY ID: 10076
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT03031730

Conditions

  • Hypercalcemia
  • Plasmacytoma
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
CarfilzomibKyprolis, PR-171Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDexTreatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)
MDM2 Inhibitor AMG-232AMG 232, AMG-232Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)

Purpose

This phase I trial studies the side effects and best dose of MDM2 inhibitor AMG-232 when given together with carfilzomib, lenalidomide, and dexamethasone in treating patient with multiple myeloma that has come back of has not responded to previous treatment. Drugs used in chemotherapy, such as MDM2 inhibitor AMG-232, carfilzomib, lenalidomide, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate safety and tolerability of MDM2 inhibitor AMG-232 (AMG-232) in combination with
      carfilzomib, lenalidomide, and dexamethasone (KRd). (Part A) II. Determine the maximum
      tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AMG-232 in combination with
      carfilzomib, lenalidomide, and dexamethasone (KRd). (Part A) III. Confirm the safety and
      tolerability of AMG 232 in combination with carfilzomib, lenalidomide, and dexamethasone
      (KRd) at MTD/tentative RP2D in a goal of 10 subjects with relapsed and/or refractory myeloma.
      (Part B)

      SECONDARY OBJECTIVES:

      I. Evaluate progressive disease (PD) effects of AMG-232 through serum MIC-1 levels. (Part A)
      II. Assess AMG-232 exposure-response relationships (PD, toxicity, and efficacy). (Part A)
      III. Evaluate the overall response rate of AMG 232 in combination with carfilzomib,
      lenalidomide, and dexamethasone (KRd) in relapsed/refractory myeloma by International Myeloma
      Working Group (IMWG) criteria. (Part B) IV. Evaluate PD effects of AMG 232 through serum
      MIC-1 levels. (Part B) V. Assess AMG 232 exposure-response relationships (PD, toxicity, and
      efficacy). (Part B)

      EXPLORATORY OBJECTIVES:

      I. To observe and record anti-tumor activity of AMG-232 in combination with carfilzomib,
      lenalidomide, and dexamethasone (KRd) in relapsed/refractory myeloma by International Myeloma
      Working Group (IMWG) criteria. (Part A) II. Evaluate ribonucleic acid (RNA) expression levels
      of relevant genes in the TP53 pathway that may predict response to therapy using pre- and
      post-treatment bone marrow biopsies. (Parts A and B)

      OUTLINE: This is a dose-escalation study of MDM2 inhibitor AMG-232.

      Patients receive MDM2 inhibitor AMG-232 orally (PO) once daily (QD) on days 1-7, carfilzomib
      intravenously (IV) over 10-30 minutes on days 1-2, 8-9, and 15-16 of cycles 1-12 and on days
      1-2 and 15-16 of cycles 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or IV on
      days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or
      unexpected toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (AMG 232, carfilzomib, lenalidomide, dexamethasone)ExperimentalPatients receive MDM2 inhibitor AMG-232 PO QD on days 1-7, carfilzomib IV over 10-30 minutes on days 1-2, 8-9, and 15-16 of cycles 1-12 and on days 1-2 and 15-16 of cycles 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity.
  • Carfilzomib
  • Dexamethasone
  • Lenalidomide
  • MDM2 Inhibitor AMG-232

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have histologically confirmed diagnosis of multiple myeloma

          -  Subjects must have measurable disease, as defined by at least one of the following:

               -  Serum monoclonal protein M-protein level >= 0.5 g/dL

               -  Urinary M-protein excretion of >= 200 mg over a 24-hour period

               -  Involved free light chain level >= 10 mg/dL, along with an abnormal free light
                  chain ratio

          -  Subjects must have disease that has relapsed and/or refractory after their most recent
             therapy, with progressive disease (PD) being defined as an increase of 25% from the
             lowest response value in any one or more of the following:

               -  Serum M-component protein (the absolute increase must be >= 0.5 g/dL) and/or

               -  Urine M-component protein (the absolute increase must be >= 200 mg/24 hours)
                  and/or

               -  Only in subjects without a measurable serum and urine M protein level: the
                  difference between involved and uninvolved free light chain (FLC) levels
                  (absolute increase) must be > 10 mg/dL

               -  Definite development of new bone lesions or soft tissue plasmacytomas or definite
                  increase in the size of existing bone lesions or soft tissue plasmacytomas

               -  Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be
                  attributed solely to the plasma cell proliferative disorder

          -  Subjects with one to three lines of therapy for their disease with a line of therapy
             defined as one or more cycles of a planned treatment program; using this definition,
             treatment with induction therapy, followed by high dose chemotherapy and autologous
             stem cell transplantation, and finally by maintenance therapy, would constitute one
             line, provided that multiple myeloma did not meet criteria for progression at any time
             during this period

          -  Subjects must have completed their most recent drug therapy directed at multiple
             myeloma in the following timeframes:

               -  Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy,
                  retinoid therapy, hormonal therapy, or investigational agent) at least 21 days
                  prior to cycle 1 day 1 (C1D1) AMG 232 + KRd

               -  Corticosteroids at least 3 weeks prior to starting AMG-232 + KRd, except for a
                  dose equivalent to dexamethasone of =< 4 mg/day

               -  Autologous stem cell transplantation at least 12 weeks prior to starting AMG-232
                  + KRd

               -  Allogeneic stem cell transplantation at least 24 weeks prior to starting AMG-232
                  + KRd, and these subjects must also NOT have moderate to severe active acute or
                  chronic graft versus host disease (GVHD)

          -  Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
             (Karnofsky >= 60%)

          -  Absolute neutrophil count (ANC) >= 1,000/mcL without growth factors within 2 week of
             initiation of treatment

          -  Platelets >= 50,000 cells/mm^3 if marrow plasmacytosis < 50% OR platelet count >=
             30,000 cells/mm^3 if marrow plasmacytosis >= 50%

          -  Hemoglobin >= 8 g/dL within 2 weeks of the initiation of treatment

          -  Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (< 2.0 x ULN for
             subjects with documented Gilbert's syndrome or < 3.0 x ULN for subjects for whom the
             indirect bilirubin level suggests an extrahepatic source of elevation)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x ULN

          -  Alkaline phosphatase < 2.0 x ULN (if liver or bone disease are present, < 3.0 x ULN)

          -  Creatinine clearance >= 50 mL/min/1.73 m^2

          -  Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of
             normal (ULN), OR international normalized ratio (INR) < 1.5

          -  Subjects who have received radiation therapy targeting > 10% of the bone marrow space
             must have completed this at least 2 weeks prior to starting therapy with AMG-232 + KRd

          -  Subjects must be able and willing to provide bone marrow biopsies/aspirates and buccal
             swab as requested by the protocol

          -  Subjects must be willing to undergo myeloma genotyping for TP53 mutation, insertion,
             or deletion at screening

          -  Subjects must have an estimated life expectancy of at least 3 months

          -  The effects of AMG 232 on the developing human fetus are unknown; for this reason and
             because lenalidomide is known to be teratogenic, women of child-bearing potential must
             commit to either abstaining continuously from heterosexual sexual intercourse or agree
             to use 2 forms of adequate contraception or continuously abstain from the time of
             informed consent for the duration of study participation through 5 weeks (women) after
             receiving the last dose of AMG 232, lenalidomide, or carfilzomib; should a woman
             become pregnant or suspect she is pregnant while she or her partner is participating
             in this study, she should inform her treating physician immediately; men treated or
             enrolled on this protocol must also agree to use adequate contraception prior to the
             study, for the duration of study participation, and 3 months after completion of AMG
             232 administration; this includes one highly effective form of contraception (e.g.
             intrauterine device [IUD], hormonal [birth control pills, injections, hormonal
             patches, vaginal rings or implants] or partner's vasectomy) and one additional
             effective contraceptive method (e.g. male latex or synthetic condom, diaphragm, or
             cervical cap)

          -  Subjects must be able to swallow medication

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Subjects with myeloma that is relapsed and/or refractory to KRd when used in
             combination defined as progression of disease while on therapy or within 60 days of
             completing therapy

          -  Subjects must show evidence of wild-type (WT) p53 status on somatic tissue specimens
             as assessed by deoxyribonucleic acid (DNA) sequencing; note that since patients with
             relapsed myeloma have a rapidly proliferating disease, patient can be enrolled and
             begin treatment prior to obtaining the results of this test; patients who are
             discovered to have a TP53 mutation will be removed from study after cycle one and can
             continue on carfilzomib, lenalidomide, and dexamethasone (KRd); all enrolled patients
             will be followed for toxicity

          -  Subjects who have not recovered from toxicities from prior anti-tumor therapy, defined
             as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE)
             version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the
             exception of alopecia (grade 2 or 3 toxicities from prior antitumor therapy that are
             considered irreversible [defined as having been present and stable for > 6 months],
             such as grade 2 chemotherapy-induced peripheral neuropathy, 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)

          -  Subjects who are receiving any other investigational agents

          -  Subjects who have undergone major surgery within 28 days of study day 1;
             vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week
             prior to starting AMG-232 + KRd

          -  Subjects with known central nervous system involvement of myeloma should be excluded
             from this clinical trial because of their poor prognosis and because they often
             develop progressive neurologic dysfunction that would confound the evaluation of
             neurologic and other adverse events

          -  Subjects with history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to AMG 232 or carfilzomib, lenalidomide, or
             dexamethasone

          -  Subjects' medication list such as herbal medicines (e.g., St. John's wort), vitamins,
             and supplements will be reviewed before starting first dose of AMG 232 and at each
             clinic visit; any potential drug interactions will be brought and discussed with the
             principal investigator; use of any known CYP3A4 substrates with narrow therapeutic
             window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide,
             quinidine, sirolimus, or terfanide) within the 14 days prior to receiving the first
             dose of AMG 232 is not permitted; other medications (such as fentanyl and oxycodone)
             may be allowed per investigator's assessment/evaluation

          -  Treatment with medications known to cause QTc interval prolongation within 7 days of
             study day 1 unless is not permitted unless approved by the sponsor; use of ondansetron
             is permitted for treatment of nausea and vomiting

          -  Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors; Note:
             low molecular weight heparin and prophylactic low dose warfarin are permitted; PT/PTT
             must meet the inclusion criteria; subjects taking warfarin must have their INR
             followed closely

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Subjects with myocardial infarction within 6 months of study day 1, symptomatic
             congestive heart failure (New York Heart Association [NYHA] class III and higher),
             unstable angina, or cardiac arrhythmia requiring medication are excluded

          -  Subjects with gastrointestinal (GI) tract disease causing the inability to take oral
             medication, malabsorption syndrome, requirement for intravenous alimentation, prior
             surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,
             Crohn's disease, ulcerative colitis)

          -  Subjects with history of bleeding diathesis

          -  Subjects with active infection requiring IV antibiotics within 2 weeks of study
             enrollment (day 1) are excluded

          -  Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B),
             positive hepatitis total core antibody with negative HBsAG (suggestive of occult
             hepatitis B), or detectable hepatitis C virus RNA by a polymerase-chain reaction (PCR)
             assay (indicative of active hepatitis C - screening is generally done by hepatitis C
             antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive);
             subjects with hepatitis B virus suppressed on therapy, and previously
             treated/eradicated hepatitis C virus are eligible for study

          -  Human immunodeficiency virus (HIV)-positive subjects positive for human
             immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive
             subjects must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  PCR-based test

          -  Pregnant women are excluded from this study because AMG 232 is an agent with the
             potential for teratogenic or abortifacient effects; because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with AMG 232, breastfeeding should be discontinued if the mother is treated
             with AMG 232; these potential risks may also apply to other agents used in this study

          -  Women who are lactating/breast feeding or who plan to breastfeed while on study
             through 1 week after receiving the last dose of study drug

          -  Subjects with prior treatment with an MDM2 inhibitor
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety parameters
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Safety parameters will include severe adverse events, treatment-emergent adverse events, physical examination findings (including Eastern Cooperative Oncology Group performance status), vital sign measurements, and standard clinical laboratory parameters (serum chemistry, hematology, urinalysis). In the Dose Escalation part, the incidence of dose limiting toxicities will also be evaluated.

Secondary Outcome Measures

Measure:Pharmacokinetic profile of MDM2 inhibitor AMG-232
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed by liquid chromatography/tandem mass spectrometric method. Descriptive statistics will be provided for selected pharmacokinetics, and pharmacodynamics data by dose and time as appropriate. Descriptive statistics on continuous data will include means, medians, standard deviations, and ranges, while categorical data will be summarized using frequency counts and percentages. Graphical summaries of the data may be presented. For MDM2 inhibitor AMG-232 , the individual pharmacokinetic parameters from a single dose will be estimated for concentration maximum (Cmax), area under the curve (AUC), T1/2, apparent Cl/F, and apparent V/F using non-compartmental or compartmental pharmacokinetic methods with the software WinNonlin.
Measure:Serum MIC-1 levels
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Each individual level will be normalized to the baseline level for that subject. changes in MIC-1 will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. MIC-1 changes will be compared across dose level using nonparametric statistical testing techniques.
Measure:Stringent complete response
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed by immunohistochemistry or 2- to 4-color flow cytometry per Clinical Relapse of Multiple Myeloma or Plasma Cell Leukemia (IMWG) criteria. A two-sided 95% exact binominal confidence interval (CI) will be calculated.
Measure:Complete response
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed by flow cytometry or DNA sequencing per IMWG criteria. A two-sided 95% exact binominal CI will be calculated.
Measure:Very good partial response
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed by immunofixation and electrophoresis per IMWG criteria. A two-sided 95% exact binominal CI will be calculated.
Measure:Partial response
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed per IMWG criteria. A two-sided 95% exact binominal CI will be calculated.
Measure:Stable disease
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed per IMWG Uniform Response criteria. A two-sided 95% exact binominal CI will be calculated.
Measure:Minor response
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Assessed per Group for Blood and Marrow Transplantation criteria. A two-sided 95% exact binominal CI will be calculated.
Measure:Myeloma response rate
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:The myeloma response rate (responses >= partial response) will also be tabulated by dose cohort and overall.
Measure:Time to response
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Time-to-event analyses will be done using Kaplan-Meier analyses.
Measure:Progression-free survival (PFS)
Time Frame:Time from the time of enrollment until documented disease progression, as determined by the Investigator using IMWG uniform response criteria, or death from any cause, whichever occurs first, assessed up to 30 days after last dose
Safety Issue:
Description:Time to response will be summarized by descriptive statistics by dose cohorts. Kaplan-Meier methods will be used to estimate PFS over time and the median duration of PFS. Subjects with no PFS event will be censored at the date of their last myeloma disease assessment.
Measure:Overall survival
Time Frame:Time from the initial administration of MDM2 inhibitor AMG-232 + KRd to death form any cause, assessed up to 30 days after last dose
Safety Issue:
Description:Time to response will be summarized by descriptive statistics by dose cohorts. Kaplan-Meier methods will be used to estimate the OS function. Subjects who do not die will be censored at the date that the subject was last known to be alive.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

December 9, 2019