Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma

In the currently proposed phase I/II study, the investigators aim to treat patients with
relapsed and/or relapsed refractory multiple myeloma (MM) who have progressed on
carfilzomib-based therapy with an FDA approved c-MET inhibitor, cabozantinib. Our hypothesis
is that the additional rescue blockade with cabozantinib added to the carfilzomib will (1) be
safe and tolerable and (2) will show activity by demonstrating objective response to
combination carfilzomib/cabozantinib therapy. In correlative studies, the investigators aim
to show that (1) the serum and marrow MUC20 levels which will be judged by genomic and flow
cytometric studies will directly correlate with primary plasma cell MUC20/c-Met pathway
activation and inversely correlate with protease inhibitor (PI) resistance; and (2) a
correlation of the gene and MUC20 expression profiles of patients with clinical outcomes may
confirm the biomarker MUC20 as a predictor of disease sensitivity to PI, and allow future
personalization of c-Met-targeted therapies, as well as combination approaches based on c-Met
inhibitors.

To be eligible for this study, patients must have been previously diagnosed with
histologically or cytologically confirmed symptomatic MM, must have measurable disease and
have had at least two, but not more than four prior lines of therapy for their disease, with
lines of therapy being separated by the presence of documented disease progression.
Additionally, patients eligible will be those who have failed carfilzomib either as a single
agent as the last form of therapy, or carfilzomib in combination with dexamethasone, or
carfilzomib in combination with revlimid and dexamethasone.

In Phase I of this study the investigators will determine the maximum tolerated dose (MTD)
among three doses. Dose limiting toxicities (DLTs) will be based solely on adverse events
that occur during cycle 1. The initial dose of cabozantinib for all patients treated on this
study will be 20 mg P.O. daily, which is designated dose level -1.

Response assessment will be performed at start and after cycle 2 using the serum and/or urine
protein electrophoresis with immunofixation and serum free light chains to assess disease
burden. Disease response quality will also be assessed after completion of three cycles of
therapy, and then every cycle after that. Bone marrow aspiration and biopsy will be performed
after the baseline sampling only to confirm the achievement of a complete remission (CR).

All patients will be closely followed for toxicity from the time of informed consent until 30
days after last administration of study medication. Adverse event and serious adverse events
will be followed until baseline or less than or equal to grade 1 levels. Every subject who
fulfills all aspects of patient eligibility who receives a partial or complete course of
chemotherapy will be evaluable for dose limiting toxicity (DLT).

Inclusion Criteria:

1. Previously diagnosed symptomatic multiple myeloma (MM), with all 3 of the following
IMWG criteria, except as noted:

- Clonal bone marrow plasma cells ≥ 10%

- A monoclonal protein in either serum or urine

- Evidence of end-organ damage that can be attributed to the underlying plasma cell
proliferative disorder (to include one of the following)

- Hypercalcemia (corrected calcium > 2.75 mmol/L or 11.5 mg/dL); OR

- Renal insufficiency attributable to myeloma (serum creatinine >1.9 mg/dL);
OR

- Anemia; normochromic, normocytic with a hemoglobin value ≥2 g/dL below the
lower limit of normal, or a hemoglobin or <10 g/dL; OR

- Bone lytic lesions, severe osteopenia or pathologic fractures.

- Patients with a biopsy-proven plasmacytoma and either a serum or urine monoclonal
protein will also be considered to have met the diagnostic criteria for multiple
myeloma in the absence of clonal marrow plasmacytosis of ≥ 10%.

- Patient with bone marrow plasma cells of ≥ 60% or serum free light chain ratio of
≥ 100 will also be considered to have met the diagnostic criteria for multiple
myeloma.

2. Patients must have measurable disease, with at least one of the following:

- Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease

- M-protein or total serum IgD ≥0.5 g/dL for IgD disease

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

- Involved free light chain level ≥10 mg/dL, with an abnormal free light chain
ratio

3. Patients must have had at least 1, but not more than 4 prior lines of therapy for
their disease, with lines of therapy separated by the presence of documented disease
progression [induction + HD chemotherapy and autologous stem cell transplant (SCT) +
maintenance therapy constitutes 1 line, provided no progression]

4. Patients must have failed carfilzomib either as a single agent as the last form of
therapy, or carfilzomib in combination with dexamethasone, carfilzomib in combination
with revlimid and dexamethasone, carfilzomib in combination with pomalidomide and
dexamethasone or carfilzomib in combination with cyclophosphamide and dexamethasone.
Patients have to have had very good tolerance to carfilzomib in the context of
described regimens, with resolved prior toxicity to grade 1 or better, and no
toxicities due to carfilzomib that required dose reductions to less than 27 mg/m².

5. Patients must have disease that has relapsed after carfilzomib therapy, with
progressive disease being defined as an increase of 25% from the lowest response value
in any one or more of the following:

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

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

- Only in patients without a measurable serum and urine M protein level: the
difference between involved and uninvolved 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

Patients with relapsed disease will be considered to be those who have had
progression, as defined above, off of any therapy, and who completed their therapy
more than 60 days prior to the finding of progression. Patients with relapsed and
refractory disease will be considered to be those who have had progression, as defined
above, while still on their last line of therapy, or who progressed within 60 days of
finishing their most recent therapy.

6. Patients must have completed their most recent drug therapy directed at MM in the
following time frames:

- Chemotherapy, biological therapy, immunotherapy, or an investigational therapy at
least 3 weeks prior to starting cabozantinib

- Corticosteroids at least 3 weeks prior to starting cabozantinib, except for a
dose equivalent to dexamethasone of ≤4 mg/day

- Nitrosoureas, nitrogen mustards, mitomycin C, or monoclonal antibodies at least 6
weeks prior to starting cabozantinib

- Autologous SCT at least 12 weeks prior to starting cabozantinib

- Allogeneic SCT at least 24 weeks prior to starting cabozantinib, and these
patients must also not have moderate to severe active acute or chronic graft
versus host disease

7. Patients must be age 19 or older (state of NE)

8. Eastern Cooperative Oncology Group performance status of 0, 1, or 2 Karnofsky ≥60%

9. Patients must have evidence of adequate bone marrow reserves, as defined by the
following:

- ANC ≥1,000 cells/mm3 without growth factors within 1 week of the initiation of
treatment

- Total WBC ≥2,000 cells/mm3 without growth factors within 1 week of the initiation
of treatment

- Hemoglobin ≥8 g/dL without red blood cell transfusions within 2 weeks of the
initiation of treatment

- Platelet counts of ≥100,000 cells/mm3 for patients who have bone marrow
plasmacytosis of <50%, or ≥50,000 cells/mm3 for patients who have bone marrow
plasmacytosis of ≥50%

10. Patients must have evidence of adequate hepatic function, as defined by the following:

- Total bilirubin ≤1.5 times the upper limit of the institutional normal values

- Total AST and ALT ≤2.5 times the upper limit of the institutional normal values

11. Patients must have evidence of adequate renal function, as defined by the following:

- Serum creatinine within the institutional normal limits, OR if the creatinine is
elevated

- Creatinine clearance (CrCl) ≥30 mL/min., as measured by a 24-hour urine
collection, or estimated by the Cockcroft and Gault formula

Any patient with urinary protein (otherwise unrelated to urinary myeloma associated
M-protein) with excretion > 3.5 g/day will be considered to have developed
nephrotic-range proteinuria, and will be taken off study.

12. Patients must have evidence of adequate cardiac function, as defined by the following:

- Absence of NYHA class II, III, or IV congestive heart failure

- Absence of uncontrolled angina or hypertension defined as sustained blood
pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study treatment

- Absence of the following in the previous 6 months:

- myocardial infarction;

- unstable angina pectoris;

- clinically-significant cardiac arrhythmias defined as grade 3 or 4 according
to NCI CTCAE, version 4.0

- stroke (including transient ischemic attack, or other ischemic event);

- thromboembolic event requiring therapeutic anticoagulation (Note: subjects
with a venous filter (eg, vena cava filter) are not eligible for this study)

- Absence of history of congenital long QT syndrome

13. Patients who have received radiation therapy (RT) must have completed this at least 4
weeks prior to starting therapy with cabozantinib, with the following exceptions:

- Local RT to enhance bone healing of a pathologic fracture within 2 weeks prior to
starting cabozantinib

- Local RT for post-fracture pain that is refractory to analgesics within 2 weeks
prior to starting cabozantinib

14. Patients who have undergone any recent major surgery within 4 weeks prior to starting
therapy with cabozantinib, with the following exceptions:

- Vertebroplasty and/or kyphoplasty must have been within 1 week prior to starting
cabozantinib

- Planned elective surgery unrelated to the patient's diagnosis of MM, such as
hernia repair, may be allowed, at the discretion of the principle investigator,
as long as it was performed within 2 weeks prior to starting cabozantinib, and
patients have recovered fully.

15. HIV seropositive patients with acceptable organ function who meet the patient
selection criteria, and who are not on combination antiretroviral therapy, and whose
absolute CD4+ count is ≥400 cells per mm3 will be eligible (HIV positive patients on
combination antiretroviral therapy will be ineligible)

16. Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (eg, male or female condom) during the course of the study
and for 4 months after the last dose of study drug(s), even if oral contraceptives are
also used. All subjects of reproductive potential must agree to use both a barrier
method and a second method of birth control during the course of the study and for 4
months after the last dose of study drug(s)

17. Female subjects of childbearing potential must not be pregnant at screening. Female
patients must be either postmenopausal, free from menses for ≥2 years, surgically
sterilized, or willing to use two adequate barrier methods of contraception to prevent
pregnancy, or must agree to abstain from heterosexual activity throughout the study.
Female patients of childbearing potential must have a negative serum (bHCG) or urine
pregnancy before the first dose of cabozantinib or carfilzomib.

18. Understand and able to willingly provide voluntary written informed consent, with the
understanding that consent may be withdrawn by the subject at any time without
prejudice to their future medical care.

Exclusion Criteria:

1. Patients who are receiving any concurrent investigational agent with known or
suspected activity against MM, or those whose adverse events due to agents
administered more than 4 weeks earlier have not recovered to grade 0 or 1.

2. Patients who have known CNS involvement with MM

3. Patients who have previously been treated with another agent targeting the MUC20/c-Met
axis, including either monoclonal antibodies to MUC20 or c-Met, or small molecule
inhibitors of c-Met.

4. Patients with a known history of allergic reactions attributed to compounds of similar
chemical or biologic composition to cabozantinib.

5. Chronic concomitant treatment with strong CYP3A4 inhibitors (eg, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort)
should be avoided because it may significantly decrease cabozantinib concentrations.
If patients are taking any strong CYP3A4 inhibitors, alternate medications with no or
minimal CYP3A4 inhibitors should be sought prior to trial enrollment.

6. Uncontrolled or ongoing/active infection, or patients with the following history:
recent history of hemorrhage or hemoptysis; dehiscence or wound healing complications
requiring medical intervention; severe hypertension that cannot be controlled (blood
pressure of > 150 systolic or > 100 diastolic mm) with anti-hypertensive therapy
within 7 days of first dose of therapy.

7. Pregnant or lactating women

8. Patients with non-secretory MM, active plasma cell leukemia, defined as either having
20% of peripheral WBC comprised of CD138+ plasma cells, or an absolute plasma cell
count of 2 x 109/L, known amyloidosis, or known POEMS syndrome

9. Patients who have required plasmapheresis and exchange less than 2 weeks prior to
initiation of therapy with cabozantinib

10. Patients with known moderate or severe hepatic impairment, active hepatitis A, B,
and/or C infection

11. Patients with a "currently active" second malignancy, other than non-melanoma skin
cancer and carcinoma in situ of the cervix. Patients are not considered to have a
"currently active" malignancy if they have completed therapy for a prior malignancy,
are disease free from prior malignancies for >5 years, and are considered by their
physician to be at less than 30% risk of relapse. Also, patients with basal cell
carcinoma of the skin, superficial carcinoma of the bladder, carcinoma of the prostate
with a current PSA value of <0.5 ng/mL, or cervical intraepithelial neoplasia are
eligible. Patients who are on hormonal therapy for a history of either prostate or
breast cancer may enroll, if there has been no evidence of disease progression during
the previous 3 years.

12. Allergy to carfilzomib or cabozantinib or any excipients

13. Uncontrolled intercurrent illness including medical, psychiatric, cognitive or other
conditions, psychiatric illness/social situations that would compromise the patient's
ability to understand the patient information, to give informed consent, to comply
with the study protocol or to complete the study or, in the judgment of the Principal
Investigator, would make the patient inappropriate for study participation.

14. The subject has experienced any of the following:

- clinically-significant GI bleeding within 6 months before the first dose of study
treatment;

- GI disorders particularly those associated with a high risk of perforation or
fistula formation including:

- Tumors invading the GI tract, active peptic ulcer disease, inflammatory
bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis,
symptomatic cholangitis or appendicitis, acute pancreatitis or acute
obstruction of the pancreatic duct or common bile duct, or gastric outlet
obstruction

- Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal
abscess within 6 months before randomization,

- hemoptysis of ≥ 0.5 teaspoon (2.5 ml) of red blood within 3 months before the
first dose of study treatment;

- any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment.

15. The subject has radiographic evidence of cavitating pulmonary lesion(s);

16. The subject has tumor invading or encasing any major blood vessels;

17. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
within 28 days before the first dose of cabozantinib;

18. QTcF > 500 msec within 1 month before the first dose of study treatment:

- Three ECGs must be performed for eligibility determination. If the average of these
three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in
this regard.

19. Inability to swallow intact tablets

20. The subject has PT/INR or PTT test ≥ 1.3 x the laboratory ULN within 7 days before the
first dose of study treatment;

21. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg,
warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg,
clopidogrel);

22. Subjects who have Carfilzomib-related posterior reversible encephalopathy syndrome
(PRES) and thrombotic microangiopathy (TMA) should not be challenged with Carfilzomib.