MDM2 Inhibitor AMG-232, Carfilzomib, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

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. (Part A) III. 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. (Part 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 courses 1-12 and on days
1-2 and 15-16 of courses 13-18, lenalidomide PO on days 1-21, and dexamethasone PO or IV on
days 1, 8, 15, and 22. Courses 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.

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 lines of therapy
being separated by the presence of documented disease progression; 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 must have normal corrected QT interval (QTc) =< 470 msec (based on average of
screening triplicates)

- 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
mucosal sample 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

- Women of child-bearing potential must agree to use adequate contraception prior to
study entry and for the duration of study participation through 5 weeks (women) after
receiving the last dose of AMG 232; 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; adequate
methods of effective birth control include sexual abstinence (men, women); vasectomy;
or a condom with spermicide (men) in combination with barrier methods, hormonal birth
control or intrauterine device (IUD) (women)

- 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; 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