Plasmacytoma, Recurrent Multiple Myeloma, Refractory Multiple Myeloma
Conditions
Brief summary
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.
Detailed description
PRIMARY OBJECTIVES: I. Evaluate safety and tolerability of MDM2 Inhibitor KRT-232 (KRT-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 KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd). (Part A) III. Confirm the safety and tolerability of KRT-232 (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 pharmacodynamic (PD) effects of KRT-232 (AMG 232) through serum MIC-1 levels. (Part A) II. Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and efficacy). (Part A) III. Evaluate the overall response rate of KRT-232 (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 KRT-232 (AMG 232) through serum MIC-1 levels. (Part B) V. Assess KRT-232 (AMG 232) exposure-response relationships (PD, toxicity, and efficacy). (Part B) EXPLORATORY OBJECTIVES: I. To observe and record anti-tumor activity of KRT-232 (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 KRT-232. Patients receive MDM2 Inhibitor KRT-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 dexamethasone sodium phosphate IV on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity. Patients undergo echocardiography during screening and bone marrow biopsy and aspiration, and blood sample collection throughout the study. After completion of study treatment, patients are followed up for 30 days.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration and biopsy
DRUGCarfilzomib
Given IV
DRUGDexamethasone
Given PO
DRUGDexamethasone Sodium Phosphate
Given IV
PROCEDUREEchocardiography
Undergo echocardiography
DRUGLenalidomide
Given PO
DRUGNavtemadlin
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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) KRT-232 (AMG 232) + KRd * Corticosteroids at least 3 weeks prior to starting KRT-232 (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 KRT-232 (AMG 232) + KRd * Allogeneic stem cell transplantation at least 24 weeks prior to starting KRT-232 (AMG 232) + KRd, and these subjects must also NOT have moderate to severe active acute or chronic graft versus host disease (GVHD) * Subjects must be \>= 18 years old. Because no dosing or adverse event data are currently available on the use of KRT-232 (AMG 232) in combination with KRd, subjects \< 18 years of age are excluded from this study * 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 (estimated glomerular filtration rate \[eGFR\]) \>= 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 KRT-232 (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 KRT-232 (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 KRT-232 (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 KRT-232 (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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Evaluate Safety and Tolerability of KRT-232 (AMG 232) in Combination With Carfilzomib, Lenalidomdie, and Dexamethasone (KRd) | at least 6 months of treatment, an average of 1 year |
| Determine Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of KRT-232 (AMG 232) in Combination With Carfilzomib, Lenalidomdie, and Dexamethasone (KRd) | at least 6 months of treatment, an average of 1 year |
Secondary
| Measure | Time frame |
|---|---|
| Evaluate PD Effects of KRT-232 (AMG 232) Through Serum MIC-1 Levels. | 30 days after last dose |
| Assess KRT-232 (AMG 232) Exposure-response Relationships (PD, Toxicity, and Efficacy). | 30 days after last dose |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORHans C Lee
University of Texas MD Anderson Cancer Center LAO
Participant flow
Recruitment details
Study opened to accrual on 10/2017 at 6 sites across ETCTN network (MD Anderson, UC Davis, UT San Antonio, UT Austin, University of Utah, Weill Cornell). Study closed to accrual 07/2024 due to uncertain development plan of MDM2 inhibitors in myeloma and slow accrual after discussion with NCI CTEP leadership and study industry collaborator, Kartos Therapeutics.
Pre-assignment details
Accrual process was slow due to various reasons including multiple screen failures for reasons including inability to perform integral biomarker testing for TP53 mutation status due to \<5% plasma cells in bone marrow biopsy at screening, TP53 mutation detected, not having measurable disease, and low creatinine clearance below eligibility threshold. 35 patients were consented, of those16 patients were eligible and dosed.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 10 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 6 / 6 | 10 / 10 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 2 / 6 | 7 / 10 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
None listed