Clinical trial NCT03201250
Conditions: Multiple Myeloma Refractory Multiple Myeloma Relapsed/Refractory Multiple Myeloma
Keywords: carfilzomib cabozantinib proteasome inhibitor resistance
Sponsor: University of Nebraska
Start date: 2018-02-21; Completion date: 2021-04-12
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In the currently proposed phase I/II study, the investigators aim to treat patients with relapsed and/or relapsed refractory Multiple Myeloma who have progressed on carfilzomib-based therapy with an FDA approved c-MET inhibitor, cabozantinib.

Detailed description:
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).

Arms: arm 1: Combination of cabozantinib, carfilzomib and dexamethasone

Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle.

Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle.

Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23)
Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Cabozantinib:

Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 Phase II: One of phase I dosing levels identified as MTD, PO daily on days 1-28

Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16

Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
UNMC IRB #434-17 Protocol Version 5.4 Dated 04-20-21 
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TITLE:   A Phase I/II Study of the c-Met Inhibitor Cabozantinib as a Targeted Strategy to 
Reverse Resistance to the Proteasome Inhibitor Carfilzomib in Refractory Multiple 
Myeloma 
 
 
 
 
Principal Investigator: 
Muhamed Baljevic, M.D. 
 
The University of Nebraska Medical Center 
Department of Internal Medicine 
Division of Hematology/Medical Oncology 
 
986840 Nebraska Medical Center  
 
Omaha, NE 68198-6840  
 
Telephone 402-559-8562, Fax 402-559-6520  
 
E-mail muhamed.baljevic@unmc.edu 
 
 
Co-Principal Investigator: 
Robert Z. Orlowski, Ph.D., M.D. 
The University of Texas M. D. Anderson Cancer Center 
 
Department of Lymphoma & Myeloma 
 
1515 Holcombe Blvd., Unit 429 
 
Houston, TX  77030 
 
Telephone 713-745-8576, Fax 713-563-5067 
 
E-mail rorlowski@mdanderson.org  
 
 
National Library of Medicine (http://clinicaltrials.gov):  NCT # 03201250 
 
NCI Protocol #: 
 
NCI-2017-02024 
 
 
Protocol IRB Approved Version: Version 4.0 Dated 01Aug2017 
 
 
 
 
 
Version 4.1  Dated 08Aug2017 
 
 
 
 
 
Version 5.0   Dated 20Feb2018 
 
 
 
 
 
Version 5.1 Dated 29Mar2019 
 
 
 
 
 
Version 5.2 Dated 23Aug2019 
 
 
 
 
 
Version 5.3 Dated 04Feb2020 
 
 
 
 
 
Version 5.4 Dated 20Apr2021 
 


 
 
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BioStatistician: 
 
Lynette Smith, PhD 
 
 
Department of Biostatistics 
 
 
UNMC College of Public Health 
 
 
984375 Nebraska Medical Center 
 
 
Omaha, NE 68198-4375 
 
 
Telephone 402-559-4112 
 
 
E-mail lmsmith@unmc.edu  
 
Pathology/Biospecimens: 
 
 
 
 
 
Clinical Studies Coordinator 
 
The University of Texas M. D. Anderson Cancer Center 
 
Department of Lymphoma & Myeloma 
 
1515 Holcombe Blvd., Unit 429 
 
Houston, TX  77030 
 
 
 
 Cabozantinib  
(Exelixis) Study reference number: IST #53  
 
Cross Reference IND# 72,596) 
 
 
Amgen Protocol Reference Number: 20159910 
 
 
IND Number: 
135624 
 
  
 


 
 
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ABSTRACT 
Much of the improvement in the median overall survival in multiple myeloma (MM) is owed to 
incorporation of proteasome inhibitors (PIs) and immunomodulators into the contemporary 
combination regimens. However, despite high remission rates in combination regimens, PI-
based therapy faced limitation in both intrinsic and acquired PI resistance. Moreover, patients 
are currently treated empirically as no markers of PI sensitivity have been identified. Resting 
on novel pre-clinical observations from studying previously established MM cell lines with 
bortezomib and carfilzomib resistance, we identified MUC20 expression as a viable biomarker 
modulating the intrinsic PI-sensitivity and/or relative resistance to PIs. In the currently 
proposed phase I/II study, we aim to treat patients with relapsed and/or relapsed refractory MM 
who have previously progressed on carfilzomib 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/cabozantnib therapy. In correlative studies, we 
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 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. 
 
 
 


 
 
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 SCHEMA 
 
 
 
 
 
 
 
 
PROTOCOL THERAPY: 28-day Cycles 
 
Cabozantinib:  
Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 
Phase II: One of phase I dosing levels identified as MTD, PO daily on days 1-28 
 
Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 
 
Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22  
(for patient age ≥ 75, acceptable to be given as 20 mg per week PO/IV) 
 
 
 


 
 
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TABLE OF CONTENTS 
Page 
Abstract .......................................................................................................................... 3 
 
Schema .......................................................................................................................... 4 
 
TABLE OF CONTENTS .................................................................................................. 5 
 
1. Objectives…………………..………………………………………………………………..7 
 
2. Background .............................................................................................................. 8 
 
3. Eligibility  ................................................................................................................ 23 
 
 
4. Registration Procedures ....................................................................................... 29 
 
5. Treatment Plan ....................................................................................................... 31 
 
6. Measurement of Effect........................................................................................... 54 
 
7. Study Calendar and Assessments ....................................................................... 57 
 
8. Drug Formulation and Procurement………….…………………….…………………58 
 
9. Toxicity and Adverse Events Guidelines …..…………………….…………………..64 
 
 
10. Statistical Considerations ..................................................................................... 70 
 
 
11. Records to be Kept ................................................................................................ 73 
 
 
12. Patient Consent ...................................................................................................... 75 
 
 
13. References ............................................................................................................. 76 
 
14. Data Collection Forms   ………………………………………………………………...81 
 
APPENDIX A 
 
    Eligibility Checklist Tool ……………………………………………………………82 
APPENDIX B 
  MDASI – MM Tool ............................................................................................ 89 
 
APPENDIX C 
EORTC QLQ-C30 TOOL ................................................................................... 91 
 
APPENDIX D 
EORTC QLQ-MY20 TOOL ................................................................................ 93 


 
 
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APPENDIX E 
ECOG PERFORMANCE STATUS SCALE ....................................................... 95 
 
APPENDIX F 
NEW YORK HEART ASSOCIATION CLASSIFICATION SYSTEM .................. 96 
 
APPENDIX G 
LIST OF POTENTIAL DRUG INTERACTIONS ................................................. 97 
 
APPENDIX H 
STUDY MEDICATION DIARY ......................................................................... 100 
 
APPENDIX I 
Child- Pugh Classifications  ............................................................................. 102 


 
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1.  
OBJECTIVES 
 
1.1. 
PRIMARY OBJECTIVES 
 
The primary objectives for this phase I/II study are: 
 
Primary Objective(s):  
 
(1) to determine the maximum tolerated dose (MTD) of daily cabozantinib given on days 1-28 
added to a capped dose of carfilzomib of 27 mg/m2 and capped dose of Dexamethasone a 40 mg 
(for patient age ≥ 75, acceptable to be given as 20 mg PO/IV) weekly every 4 weeks in patients 
with relapsed and refractory (RR) multiple myeloma (MM) who have lost response to carfilzomib 
 
 
(2) to estimate the overall response rate (ORR) of patients with RR MM treated with the addition 
of cabozantinib to carfilzomib.  
 
1.2. 
SECONDARY OBJECTIVES 
 
The secondary objectives for this phase II study are: 
 
(1) to identify biological correlates of clinical outcomes and toxicity, including the measurement of 
MUC20 levels at enrollment and after cycle 2, and activation status of the c-MET/ERK-
1/2/ELK1/POMP pathway in primary MM cells at baseline and after each cycles of therapy on 
protocol, as defined by flow cytometry and GEP data;  
 
(2) to estimate progression free survival (PFS), median duration of response (DOR), and median 
time to next treatment;  
 
 
1.3. 
EXPLORATORY OBJECTIVES 
 
The exploratory objectives for this phase I/II study are: 
 
(1) To evaluate the symptom burden of RR MM patients undergoing therapy with addition of 
cabozantinib to carfilzomib in patients who have lost response to proteasome inhibition with 
carfilzomib, using the M. D. Anderson Symptom Inventory (MDASI) and its multiple myeloma 
module (MDASI-MM; please see Appendix B) 
 
(2) To evaluate the impact of therapy with cabozantinib in combinbation with carfilzomib in 
patients who have lost response to proteasome inhibition with carfilzomib in the RR MM setting 
on patient reported outcomes using the European Organization for Research on the Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (QLQ-C30; please see Appendix 
C), and the myeloma-specific module QLQ-MY20 (please see Appendix D) 
 
(3) To evaluate the impact of therapy with cabozantinib for RR MM on the ability to collect stem 
cells in any patients who go on to undergo subsequent stem cell mobilization


 
 
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2. BACKGROUND 
 
2.1 
STUDY DISEASE 
 
Multiple myeloma is characterized by an expansion of a clonal population of plasma cells in the 
bone marrow1, and is the second most commonly diagnosed hematologic malignancy.  Statistics 
from the American Cancer Society indicate that, in 2010, a total of 20,180 patients will be 
diagnosed with this plasma cell dyscrasia in the United States, including 11,170 men, and 9,010 
women2.  Notably, while the incidence of this disease appears to be stable, the total number of 
new cases yearly has more than doubled since 1983, when 9,600 patients were diagnosed3, 
indicating that myeloma is becoming an increasing health care burden in the United States.  This 
increase is in part due to the aging of the population, in that the average age at diagnosis of 
myeloma is usually 65-701.  Common disease-related symptoms include bony pain, due to either 
lytic disease or pathologic fractures, such as of the ribs or vertebrae; fatigue, due generally to 
anemia; renal insufficiency, due to cast nephropathy or amyloidosis, among others; and 
hypercalcemia, due to renal insufficiency and osteolysis.  Other symptoms can include frequent 
infections due to granulocytopenia, functional hypogammaglobulinemia, and impaired cell-
mediated immunity; peripheral neuropathy, due to amyloidosis or nerve root impingement; and 
manifestations of hyperviscosity, including dizziness, headaches, congestive heart failure, and 
bleeding diatheses1. 
 
Treatment for multiple myeloma is directed at reducing the total body disease burden, and 
therefore the symptoms associated with this disease process.  Patients typically receive some 
kind of induction therapy regimen after developing symptomatic disease, which is often 
determined in part by whether they are candidates for high dose chemotherapy with autologous 
stem cell transplantation (ASCT).  For those patients who are younger and/or fitter, and could be 
ASCT candidates, induction will typically consist of a regimen that avoids the use of the alkylating 
agent melphalan to avoid stem cell damage.  Active and widely available chemotherapeutics in 
this setting include traditional cytotoxic agents, such as the alkylating agent cyclophosphamide, 
which is not toxic to stem cells, anthracyclines such as doxorubicin, corticosteroids such as 
dexamethasone or prednisone, and the microtubule targeting drug vincristine1.  In addition, a 
number of novel drugs have been introduced over the past ten years that were initially validated 
in the relapsed and/or refractory setting, including immunomodulatory drugs such as thalidomide 
and lenalidomide4, and proteasome inhibitors such as bortezomib5.  These are now often 
incorporated into up-front regimens in combination with each other, as well as with some of the 
older cytotoxic agents.  Among these various options, the National Comprehensive Cancer 
Network currently most strongly recommends the regimens of bortezomib with dexamethasone6, 
bortezomib with doxorubicin and dexamethasone7, bortezomib with thalidomide and 
dexamethasone8, or lenalidomide with dexamethasone9 prior to transplantation. 
 
For those patients who are not ASCT candidates, usually because of advanced age, or 
compromised organ function and/or performance status, induction therapy will also typically 
incorporate novel agents and traditional cytotoxics, but are more likely to also include melphalan1.  
In this setting, the National Comprehensive Cancer Network currently most strongly recommends 
the regimens of bortezomib with melphalan and prednisone10, thalidomide with melphalan and 
prednisone11, and lenalidomide with dexamethasone9. 
 
With the introduction of novel agents, the outcomes for patients with multiple myeloma in both the 
up-front, and relapsed and/or refractory settings, have been improving12–14.  Indeed, some studies 
suggest that median survival may have been increased from a previous average of three to four 
years, to seven to eight years, and that longer survival is now commonly possible, especially in 


 
 
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patients with good risk cytogenetic features who achieve a complete remission (CR).  
Unfortunately, myeloma is still felt to be incurable in the vast majority of patients, and even those 
who achieve a CR with front-line standard or high dose therapies eventually relapse.  Options at 
that point include retreatment with their prior induction regimen, and the use of thalidomide15 and 
lenalidomide16–18, as well as bortezomib19–22, either alone, or in various combinations.  Second-
line therapy can in many cases reestablish a complete remission, but this is typically of shorter 
duration than previously, due in part to the emergence of more drug-resistant disease clones.  As 
a result, myeloma is characterized clinically by multiple relapses and decreasing remission 
durations with each additional line of therapy23,24.  This indicates the need to continue to develop 
more novel and targeted agents that could be incorporated into our chemotherapeutic 
armamentarium against myeloma, and which could be used in a rational, molecularly adapted 
manner. 
 
2.2 
Cabozantinib 
 
Receptor tyrosine kinases (RTKs) have emerged as an important class of molecular targets for 
anti-cancer therapy.  The encouraging results from agents such as imatinib mesylate (Gleevec) 
against cancers with the constitutively active Bcr-Abl mutation, as well as erlotinib, an inhibitor of 
mutated and overexpressed epidermal growth factor (EGF) receptor kinase, have provided 
important clinical evidence that molecularly targeted RTK inhibitors are efficacious and can have 
a significant and broad effect against various cancers.  As more RTKs are implicated in the 
pathophysiology of oncogenesis, the notion has been put forward that the signal transduction 
pathways that are served by these RTKs become dominant in initiating and maintaining the pro-
proliferative and anti-apoptotic phenotype of the transformed cell.  Indeed, there is growing 
evidence that dysregulated RTK signaling in cancer cells may result in so-called “oncogene 
addiction,” providing the opportunity to selectively kill cancer cells by ablating RTK signaling 
pharmacologically25.   
 
The c-Met RTK mediates the signals for a variety of physiological processes that have 
implications for oncogenesis, including migration, invasion, cell proliferation, and angiogenesis.  
A wide variety of human cancers exhibit constitutively dysregulated c-Met activity, either through 
over-expression of the c-Met kinase, activating mutations in c-Met, or increased autocrine or 
paracrine secretion of the c-Met ligand hepatocyte growth factor/scatter factor (HGF/SF).  These 
alterations have been strongly implicated in tumor progression and metastasis in a variety of 
cancers, and a high constitutive activation of the c-Met RTK has been correlated with poor clinical 
prognosis26,27. 
 
c-Met can be activated in both a ligand-dependent manner, by the overexpression of c-Met and/or 
its ligand HGF, or a ligand-independent manner as in the case of activating mutations of c-Met 
such as those described in sporadic and hereditary papillary renal carcinoma26.  Activation and 
autophosphorylation of c-Met results in the binding and phosphorylation of adaptor proteins such 
as Gab1, Grb2, Shc and c-Cbl, and results in the subsequent activation of signaling pathways, 
including the PI3K/Akt, FAK, STAT and Ras/MEK/Erk pathways that play various roles in cell 
survival, proliferation, invasion, and angiogenesis28,29.  In the melanocyte lineage, c-Met 
expression is upregulated by microphthalmia-associated transcription factor (MITF), which has 
been implicated in the oncogenesis of melanoma and other cancers30,31.  
 
The presence of c-Met in most cancers, and its role in controlling multiple signal transduction 
pathways involved in tumor growth render this enzyme a logical therapeutic target for human 
cancer. 
 


 
 
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Cabozantinib is a FDA approved potent RTK inhibitor with selectivity against RET, MET, 
VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2 c-Met RTK, as determined by 
biochemical and cellular assays.  A comprehensive review of cabozantinib can be found in the 
cabozantinib Exelixis FDA package insert (2012)32. 
 
2.2.1 NON-CLINICAL PHARMACOLOGY 
 
In Vitro Efficacy 
 
Cabozantinib (XL184) is a potent inhibitor of MET and VEGFR2 that also inhibits RET, KIT, AXL, 
and FLT3, all of which have been implicated in tumor pathogenesis. Cabozantinib inhibits MET 
and VEGFR2 with IC50 values of 1.3 and 0.035 nmol/L respectively, while it also strongly inhibited 
KIT, RET, AXL, TIE2, and FLT3at IC50 values of 4.6, 5.2, 7, 14.3, and 11.3 nmol/L, respectively. 
IC50 determinations conducted at various concentrations of ATP revealed that cabozantinib is an 
ATP-competitive inhibitor of MET, VEGFR2, TIE2, and FLT3.  
 
Cabozantinib inhibits endothelial cell tubule formation in vitro: HMVEC cells were incubated with 
VEGF in the presence of cabozantinib and tubule formation visualized by immunostaining for 
CD31. Cabozantinib inhibited tubule formation with an IC50 value of 6.7 nmol/L without 
cytotoxicity, indicating that cabozantinib exerts an antiangiogenic rather than cytotoxic effect. 
 
Cabozantinib potently inhibited HGF-induced migration (IC50 31 nmol/L) and invasion (IC50 9 
nmol/L) of B16F10 cells. VEGF- and HGF-mediated migration of proangiogenic murine MS1 
endothelial cells were also sensitive to cabozantinib with IC50 values of 5.8 and 41 nmol/L, 
respectively33. 
 
Cabozantinib inhibits tumor cell proliferation in a variety of tumor types. The effect of cabozantinib 
on proliferation was evaluated in a number of human tumor cell lines. SNU-5 
and Hs746T cells harboring amplified MET34 were the most sensitive to cabozantinib (IC50 = 19 
and 9.9 nmol/L, respectively); however, SNU-1 and SNU-16 cells lacking MET amplification were 
more resistant (IC50 = 5,223 and 1,149 nmol/L, respectively). MDAMB-231 and U87MG cells 
exhibited comparable levels of sensitivity to cabozantinib (IC50 = 6,421 and 1,851 nmol/L, 
respectively), whereas H441, H69, and PC3 cell lines were the least sensitive to cabozantinib 
with IC50 values of 21,700, 20,200, and 10,800 nmol/L, respectively. In addition, BaF3 cells 
expressing human FLT3-ITD, an activating mutation in acute myelogenous leukemia35, were 
sensitive to cabozantinib (IC50 = 15 nmol/L) when compared with wild-type BaF3 cells (IC50 = 
9,641 nmol/L). 
 
In Vivo Efficacy 
 
Cabozantinib inhibits MET and VEGFR2 phosphorylation in vivo.  A single 100 mg/kg oral dose 
of cabozantinib resulted in inhibition of phosphorylation of MET 2 to 8 hours post dose in H441 
tumors that harbor constitutively phosphorylated MET. This result is consistent with data showing 
the sensitivity of these cells to inhibitors selective for MET and MET knockdown by siRNA28,36. 
 
This effect was reversible, as MET phosphorylation returned to basal levels by 48 hours after 
treatment. In separate experiments, cabozantinib inhibited in vivo stimulation of MET 
phosphorylation by HGF in liver hepatocytes and VEGF-stimulated phosphorylation of 
FLK1 with inhibition of both targets sustained through 8 hours postdose. Furthermore, 
cabozantinib eliminated endogenous levels of phosphorylated FLK1 that are present in the 
absence of VEGF stimulation. 


 
 
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Plasma concentrations of cabozantinib associated with maximal and sustained inhibition of MET 
and FLK1 were 17 - 34 mmol/L, greater than 3-fold above the MET cellular phosphorylation, VEGF 
tubule formation, and HGF invasion IC50 values described. 
 
Cabozantinib disrupts tumor vasculature and promotes tumor and endothelial cell death.  
Antiangiogenic-sensitive MDA-MB-231 cells expressing MET and VEGF were administered to 
tumor-bearing animals which were treated with a 100-mg/kg oral dose of Cabozantinib. 
Cabozantinib significantly increased tumor hypoxia and apoptosis when compared with vehicle-
treated tumors. Cabozantinib induced cell death not only in tumor cells but also in endothelial 
cells in the tumor vasculature. These results showed that cabozantinib disrupts tumor vasculature 
by inducing endothelial cell death that negatively impacts tumor viability33. 
 
The in vivo efficacy of cabozantinib was evaluated in human tumor models in rodents over a 
period of time that corresponded to exponential tumor growth of each model. Cabozantinib 
treatment resulted in significant tumor growth inhibition of MDA-MB-231 tumors (P < 0.001) for all 
doses when compared with vehicle-treated tumors. Dose-dependent inhibition was observed for 
the 3- and 10-mg/kg doses (P < 0.01). Continuous treatment was associated with plasma 
concentrations of 9,000 to 16,000 nmol/L, which was ~2-fold above IC50 values for cellular 
proliferation and tubule formation with MDA-MB-231 conditioned media. Cabozantinib inhibited 
growth of H441 tumors at all doses (P < 0.001), with dose-dependent inhibition observed for the 
10- and 30- mg/kg doses. The 60-mg/kg dose resulted in significant tumor regression (33%, P < 
0.005) when compared with pre-dose tumor weights. The antitumor effect of cabozantinib in the 
MET-expressing rat C6 glioma cell line was also determined. Cabozantinib inhibited tumor growth 
(P < 0.001) for all doses when compared with vehicle-treated tumors. Moreover, the 3- and 10-
mg/kg doses resulted in significant tumor regression (62 and 85%, P < 0.0001) when compared 
with pre-dose tumor weights33.  
 
On a body weight dosage basis, cabozantinib plasma exposures ranged from 6- to 10-fold higher 
in rats than in mice, which accounted for lower doses inducing tumor growth inhibition/regression 
in rats than in mice. 
 
2.2.2 CLINICAL PHARMACOKINETICS 
 
A population pharmacokinetic analysis of cabozantinib (COMETRIQ) was performed using data 
collected from 289 patients with solid tumors including MTC following oral administration of 140 
mg daily doses. The predicted effective half-life is approximately 55 hours, the oral volume of 
distribution (V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to 
be 4.4 L/hr32. 
 
Absorption and Distribution: 
Following oral administration of cabozantinib, median time to peak cabozantinib plasma 
concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily dosing of cabozantinib at 
140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) 
compared to a single dose administration; steady state was achieved by Day 15. Cabozantinib is 
highly protein bound in human plasma (≥ 99.7%). A high-fat meal increased Cmax and AUC values 
by 41% and 57%, respectively relative to fasted conditions in healthy subjects administered a 
single 140 mg oral cabozantinib dose32. 
 
 
 


 
 
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Metabolism and Elimination: 
 
Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the formation of 
the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on 
cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, 
CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite 
formation. Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy 
subjects, approximately 81% of the total administered radioactivity was recovered with 54% in 
feces and 27% in urine32.  
 
As such, because there is a potential for interaction of cabozantinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  The 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes. 
 
 
2.2.3 NON-CLINICAL TOXICOLOGY 
 
In an embryo-fetal development study in which pregnant rats were administered daily doses of 
cabozantinib during organogenesis, increased loss of pregnancy compared to controls was 
observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the 
recommended dose). Findings included delayed ossifications and skeletal variations at doses 
equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at 
the recommended dose)32. 
 
Please refer to investigators brochure for the remainder of the non-clinical toxicology. 
 
2.2.4 CLINICAL EXPERIENCE 
 
The pharmacokinetics, metabolism, safety, and efficacy of cabozantinib have been investigated 
in multiple phase 1 and phase 2 clinical trials in cancer patients.  Two phase I dose escalation 
trials have defined the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) 
for continuous doses of cabozantinib as a single agent.  
 
Pivotal phase III trial in medullary thyroid cancer patients has since also been completed.    
 
 
2.2.5 PHASE I STUDIES 
 
A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced 
solid tumors, including patients with medullary thyroid cancer (MTC)37. Primary end points 
included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) 
determination. Additional end points included RECIST (Response Evaluation Criteria in Solid 
Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.  
Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-
limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, 
ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. 
Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. 
Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 
patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had 


 
 
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stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed 
partial response in 68% of patients with MTC. 
 
Cabozantinib was also evaluated in a cohort of heavily pretreated patients with metastatic 
differentiated thyroid cancer (DTC)38. This single-arm open-label phase I trial assessed the safety, 
tolerability, and antitumor activity of cabozantinib in DTC patients taking part in a drug-drug 
interaction study. Adult patients with histologically confirmed metastatic or surgically unresectable 
DTC (including papillary, follicular, or Hürthle cell) were enrolled. Patients received daily oral 
dosing of 140 mg cabozantinib. Safety was assessed by evaluation of adverse events (AEs), vital 
signs, electrocardiograms, laboratory tests, and concomitant medications. Tumor response by 
magnetic resonance imaging or computed tomography scan was investigator assessed using 
Response Evaluation Criteria In Solid Tumors (RECIST) v1.0. The study enrolled 15 patients who 
had failed standard radioactive iodine therapy. Patients had received a median of two prior 
systemic agents, and 11 patients (73%) had previously received at least one VEGF pathway 
inhibiting therapy. Common AEs included diarrhea, nausea, fatigue, and decreased appetite. 
Partial response was reported in eight patients (53%). Median progression-free survival (PFS) 
and median overall survival (OS) were not reached. 
 
2.2.6 PHASE II STUDIES 
Cabozantinib was subsequently evaluated for the activity in patients with castration-resistant 
prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. 
Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 
weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective 
response rate at 12 weeks and PFS after random assignment39. One hundred seventy-one men 
with CRPC were enrolled. Random assignment was halted early based on the observed activity 
of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 
68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. 
The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-
one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 
weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) 
with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-
linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable 
patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a 
decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), 
hypertension (12%), and hand-foot syndrome (8%). Cabozantinib was hence shown to have 
clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, 
resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use 
 
2.2.7 PHASE III STUDIES 
 
The safety and efficacy of cabozantinib was assessed in an international, multi-center, 
randomized, double-blind, controlled trial of 330 patients with metastatic medullary thyroid 
carcinoma (MTC)40. Patients were required to have evidence of actively progressive disease 
within 14 months prior to study entry confirmed by an Independent Radiology Review Committee 
(IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were 
randomized (2:1) to receive cabozantinib 140 mg (n = 219) or placebo (n = 111) orally once daily, 
without food, until disease progression determined by the treating physician or until intolerable 
toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine 
kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The 
main efficacy outcome measures of progression-free survival (PFS), objective response (OR), 


 
 
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and response duration were based on IRRC-confirmed events using modified RECIST criteria. 
Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years 
or older, 89% were white, 54% had a baseline ECOG performance status of 0, 92% had 
undergone a thyroidectomy, and 48% were reported to be RET mutation positive according to 
research-use assays. Twenty-five percent (25%) had two or more prior systemic therapies and 
21% had been previously treated with a TKI. A statistically significant prolongation in PFS was 
demonstrated among cabozantinib-treated patients compared to those receiving placebo [HR 
0.28 (95% CI: 0.19, 0.40); p <0.0001], with median PFS times of 11.2 months and 4.0 months in 
the cabozantinib and placebo arms, respectively. Partial responses were observed only among 
patients in the COMETRIQ arm (27% vs. 0; p<0.0001). The median duration of objective 
responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with cabozantinib. There 
was no statistically significant difference in OS between the treatment arms at the planned interim 
analysis. Toxicities >20% in the cabozantinib treatment arm included diarrhea (63.1% all grade, 
15.9% grade ≥ 3), palmar-plantar erythrodysesthesia (hand-foot syndrome; 50% all grade, 12.5% 
grade ≥ 3), decreased weight (47.7% all grade, 4.7% grade ≥ 3), decreased appetite (45.8% all 
grade, 4.7% grade ≥ 3), nausea (43% all grade, 1.4% grade ≥ 3), fatigue (40.7% all grade, 9.3% 
grade ≥ 3), dysgeusia (34.1% all grade, 0.5% grade ≥ 3), hair color changes (33.6% all grade, 
0.5% grade ≥ 3), hypertension (32.7% all grade, 8.4% grade ≥ 3), stomatitis (29% all grade, 1.9% 
grade ≥ 3), constipation (26.6% all grade, 0% grade ≥ 3), hemorrhage (25.2% all grade, 3.3% 
grade ≥ 3), vomiting (24.3% all grade, 2.3% grade ≥ 3), mucosal inflammation (23.4% all grade, 
3.3% grade ≥ 3), asthenia (21% all grade, 5.6% grade ≥ 3), dysphonia (20.1% all grade, 0% grade 
≥ 3). Serious adverse events (SAEs) were more frequent in cabozantinib- versus placebo-treated 
patients (42.1% v 22.9%). SAEs that occurred at a ≥ 2% frequency in cabozantinib- versus 
placebo-treated patients included mucosal inflammation (2.8% v 0%), hypocalcemia (2.8% v 0%), 
pulmonary embolism (2.3% v 0%), and hypertension (2.3% v 0%). AEs (not specified in report) 
were listed as the primary reason for treatment discontinuation in 16% of cabozantinib-treated 
patients and in 8% of placebo-treated patients. Most deaths were attributed to disease 
progression (77% in the cabozantinib arm and 80% in the placebo arm). 
 
More recently, cabozantinib versus Everolimus was compared in advanced renal-cell carcinoma 
in an open-label phase III event-driven trial (METEOR)41. Investigators randomly assigned 658 
patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. 
The primary end point was PFS. Secondary efficacy end points were OS and objective 
response rate (ORR). Median PFS was 7.4 months with cabozantinib and 3.8 months with 
everolimus. The rate of progression or death was 42% lower with cabozantinib than with 
everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The ORR 
was 21% with cabozantinib and 5% with everolimus (P<0.001).  Median overall survival was 
21·4 months (95% CI 18·7-not estimable) with cabozantinib and 16·5 months (14·7-18·8) with 
everolimus (hazard ratio [HR] 0·66 [95% CI 0·53-0·83]; p=0·00026). Cabozantinib treatment 
also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41-0·62]; p<0·0001) and 
objective response (17% [13-22] with cabozantinib vs 3% [2-6] with everolimus; p<0·0001) per 
independent radiology review among all randomised patients84.   AEs were managed with dose 
reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of 
those who received everolimus. Discontinuation of study treatment owing to adverse events 
occurred in 9% of the patients who received cabozantinib and in 10% of those who received 
everolimus.  
 
Toxicities >20% in the cabozantinib treatment arm included diarrhea (74% all grade, 11% grade 
≥ 3), fatigue (56% all grade, 9% grade ≥ 3), nausea (50% all grade, 4% grade ≥ 3), decreased 
appetite (46% all grade, 2% grade ≥ 3), palmar-plantar erythrodysesthesia (hand-foot syndrome; 
42% all grade, 8% grade ≥ 3), hypertension (37% all grade, 15% grade ≥ 3), vomiting (32% all 


 
 
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grade, 2% grade ≥ 3), decreased weight (31% all grade, 2% grade ≥ 3), constipation (25% all 
grade, <1% grade ≥ 3), dysgeusia (24% all grade, 0% grade ≥ 3), stomatitis (22% all grade, 2% 
grade ≥ 3).            
 
The most common adverse events (any grade) leading to dose reductions with cabozantinib were 
diarrhea (16%), the palmar–plantar erythrodysesthesia syndrome (11%), and fatigue (10%), and 
the most common with everolimus were pneumonitis (4%), fatigue (3%), and stomatitis (3%). 
Grade 5 adverse events occurred in 22 patients (7%) in the cabozantinib group and in 25 patients 
(8%) in the everolimus group and were primarily related to disease progression. Grade 5 events 
that were considered to be treatment-related occurred in 1 patient in the cabozantinib group 
(death not otherwise specified) and in 2 patients in the everolimus group (aspergillus infection 
and aspiration pneumonia). 
 
 
2.2.8 PHARMACOKINETICS 
 
A population pharmacokinetic analysis of cabozantinib was performed using data collected from 
289 patients with solid tumors including MTC following oral administration of 140 mg daily 
doses. The predicted effective half-life is approximately 55 hours, the oral volume of distribution 
(V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to be 4.4 
L/hr32. 
 
Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of 
both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor 
of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM) preparations. IC50 values 
>20 M were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes in both recombinant and 
HLM assay systems. 
 
Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (i.e., 75-100% 
of CYP1A1 positive control β-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities. 
 
Cabozantinib at steady-state plasma concentrations (100 mg/day daily for a minimum of 21 
days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure 
(Cmax and AUC) in patients with solid tumors. 
 
P-glycoprotein Inhibition: Cabozantinib is an inhibitor (IC50 = 7.0 M), but not a substrate, of P-gp 
transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, 
cabozantinib may have the potential to increase plasma concentrations of co-administered 
substrates of P-gp. 
 
The safety and effectiveness of cabozantinib in pediatric or geriatric patients aged 65 years and 
over have not been studied. 
 
Cabozantinib should be used with caution in subjects with mild or moderate hepatic impairment 
(Child-Pugh class A and B, Appendix I). These subjects will be monitored closely for potential 
treatment-emergent drug toxicity that may necessitate a dose hold or reduction. If starting dose 
of Cabozantinib is >40 mg daily in patients with mild to moderate hepatic or renal impairment 
(Level +1 dose), candidacy for clinical trial will be discussed on a case-to-case basis. 
Cabozantinib will not be used in patients with severe hepatic impairment (Child-Pugh Class C)85.   
 


 
 
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No dose adjustment is recommended for patients with mild or moderate renal impairment. There 
is no experience with cabozantinib in patients with severe renal impairment. 
 
Detailed preliminary pharmacokinetic data can be found in the most recent Cabozantinib 
Investigator’s Brochure (2012). 
 
 
2.3 
Carfilzomib 
 
2.3.1. Carfilzomib Background 
 
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the Chymotrypsin-
like active site of the 20S proteasome. Carfilzomib is structurally and mechanistically distinct from 
the dipeptide boronic acid proteasome inhibitor bortezomib (Velcade®). In addition, when 
measured against a broad panel of proteases including metallo, aspartyl, and serine 
proteases, carfilzomib demonstrated less reactivity against non-proteasomal proteases 
when compared to bortezomib42,43. 
 
2.3.2. Carfilzomib Toxicology Studies 
 
In the initial Good Laboratory Practice (GLP)‐compliant toxicity studies done by the drug maker, 
Onyx, carfilzomib was administered to rats and monkeys as two complete two week cycles of 
QDx5 for five days with nine days rest44. Administration to rats at 12 mg/m2, the severely toxic 
dose in 10% of animals (STD10), caused > 90% proteasome inhibition in red blood cells one hour 
after dosing. Overall, stronger inhibition of the proteasome and longer duration of inhibition was 
tolerated with carfilzomib compared with bortezomib. Daily administration of bortezomib at anti‐
tumor doses is not tolerated in animals, and therefore daily bortezomib has not been given in the 
clinic. A dose-dependent decrease in proteasome activity was demonstrated in animals, and 
equivalent levels of proteasome inhibition were achieved with administration of carfilzomib as 
either an intravenous (IV) push or an IV infusion. The DLTs of carfilzomib in both the rat and 
monkey 28 day GLP toxicity studies included toxicity to the gastrointestinal tract, bone marrow, 
pulmonary, and cardiovascular systems. No behavioral or histopathological signs of neurotoxicity 
were observed, and carfilzomib does not cross the blood‐brain barrier. In 6‐month rat and 9‐month 
chronic toxicity studies, carfilzomib was administered on Days 1, 2, 8, 9, 15, and 16 of a 28‐day 
cycle, mimicking the active anti‐tumor regimen being used in ongoing Phase II studies in myeloma 
and solid tumors44. Tolerability was excellent, with no evidence of peripheral (or central) 
neurotoxicity, including neuropathology, observed, even at high doses. This is in stark contrast to 
that observed with bortezomib45. DLTs included effects on the gastrointestinal, renal, pulmonary, 
and cardiovascular systems and appeared to relate to Cmax effects. Of note, neutropenia was not 
observed; rather, transient neutrophilia was seen following acute dosing. Renal, cardiovascular 
and gastrointestinal toxicities were similar to those observed with bortezomib. Finally, cyclical 
thrombocytopenia, likely due to inhibition of platelet budding from megakaryocytes, was similar to 
that seen with bortezomib. Proteasome inhibition in the blood in excess of 90% was achievable 
at well‐tolerated doses, which contrasts with the ~70% proteasome inhibition achievable with 
bortezomib at its maximum tolerated dose (MTD). In summary, these animal toxicity studies 
support the tolerability of carfilzomib in clinical studies, even on intensive dosing schedules and 
at doses achieving proteasome inhibition in excess of what can be achieve with bortezomib at its 
MTD on a less intensive schedule. 
 


 
 
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2.4 
RATIONALE FOR TARGETING c-MET IN CARFILZOMIB RESISTANT 
MULTIPLE MYELOMA 
 
Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells and it remains 
incurable despite rapidly progressive armamentarium of therapeutic agents. Much of the 
improvement in the median overall survival in patients with MM is owed to incorporation of 
proteasome inhibitors (PIs)46 and immunomodulators (IMiDs)47,48 into the contemporary 
combination regimens. 
 
Bortezomib is the first PI to gain regulatory approval when it became available as a single agent 
in the relapsed and/or refractory setting based on data from series of phase I through III trials19–
21, and was subsequently approved as part of front-line therapy with melphalan and prednisone10. 
Despite high remission rates in combination regimens, bortezomib-based therapy faced limitation 
in both intrinsic and acquired bortezomib resistance49. Mutation and overexpression of the 
proteasome subunit PSMB5 (proteasome subunit β type 5) have been demonstrated to be an 
important mechanism of bortezomib resistance50,51. Other causative factors play a role in 
development of proteasome resistance including persistent implication of NF-κB signaling 
pathways in in vitro and in vivo studies52, antioxidant signaling in MM patient samples as well as 
MM cell lines53,54 as well as bone marrow microenvironment with IGFs (insulin-like growth 
factors)55,56 and Btk (Bruton’s tyrosine kinase) pathway57.  
 
A more durable inhibition of the proteasome compared to reversible effect of bortezomib is 
achieved with second generation proteasome inhibitor Carfilzomib (Kyprolis), which is a peptide 
epoxy-ketone that binds the N-terminal threonine active site of the β5 subunit of the proteasome 
in an irreversible manner58,59. The efficacy of single-agent carfilzomib in patients with disease 
refractory to bortezomib and IMiD therapy was established in the PX-171-003-A1 study, a 
multicenter single-arm phase II trial, with an overall response rate of 24%, and the median 
duration of response of 7.8 months60. In a phase II trial (PX-171-004) of bortezomib naïve patients, 
the response rate with single-agent carfilzomib was approximately 50%61. Importantly, in the 
process of emergence of PI resistance that is poorly understood, even though carfilzomib shows 
activity in bortezomib resistant multiple myeloma cell lines and patient samples62, resistance 
inevitably emerges to carfilzomib as well.  
 
Given the need to identify mechanisms and develop biomarkers that could help guide the therapy 
past the point of proteasome resistance, as well as provide novel targets to overcome resistance, 
our group has made novel observations from studying previously established MM cell lines with 
bortezomib and carfilzomib resistance. We found that MUC20 expression may be a viable 
biomarker modulating the intrinsic proteasome inhibitor-sensitivity or relative–resistance. MUC20 
levels were decreased in MM cell lines resistant to bortezomib or carfilzomib, and differential 
effect on MM cell viability was demonstrated with either shRNA knockdown or lentiviral over-
expression of MUC20 (Figure 1.). Decreased levels of MUC20 lead to higher signaling through 
the c-MET/ERK-1/2/ELK1/POMP axis, which enhances the proteasome capacity and assembly, 
resulting in the ELK1-regulated enhancement of the POMP (proteasome maturation protein) 
expression, which in turn increases the assembly of the entire 20S proteasome, thereby reducing 
sensitivity to proteasome inhibition by bortezomib or carfilzomib. Crucially, MET inhibitor 
Cabozantinib was able to increase the sensitivity of PIs both in vitro (Figure 2.) and in vivo (data 
not shown), allowing for rescue of PI sensitivity in relapsed refractory MM. To validate the MUC20 
as a candidate biomarker in the assessment of MM sensitivity to PI and overall outcome, samples 
from Millennium and Arkansas database in patients treated with bortezomib in the relapsed and 
relapsed and refractory settings were analyzed for MUC20 expression levels (Figure 3.). Patients 
who had higher expression of MUC20 had higher (CR+PR+MR) rate, which resulted in improved 


 
 
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PFS and OS. This analysis ultimately demonstrates that higher expression of MUC20 
corresponded to superior OS in the myeloma patients, validating MUC20 as a viable and accurate 
indicator of not only PI sensitivity but also overall outcome in MM patients.  
 
In the currently proposed study, we aim to treat the patients with RR MM who previously 
progressed on Carfilzomib-based therapy with an FDA approved c-MET inhibitor Cabozantinib. 
We hope to be able to rescue the PI by Carfilzomib in these patients, rendering them sensitive 
to the therapy that has proven to result in improved outcomes in MM patients.  
 


 
 
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 Figure 1. MUC20 
expression impacted PI 
sensitivity in myeloma cell 
lines. 
A. Using qPCR to detect 
MUC20 mRNA content in CR 
myeloma cells including OPM-
2/CR, ANBL-6/CR, KAS-
6/1/CR, U266/CR (left panel) 
and BR cells including OPM-
2/BR, ANBL-6/BR, KAS-
6/1/BR and RPMI 
8226/BR(right panel) 
compared with their WT 
counterparts. Numbers 
represent relative quantitation 
(RQ) normalized to GAPDH (# 
p < 0.01 vs. WT).  
B. Using Western blot to 
evaluate MUC20 protein levels 
in these same cell lines, and 
compared to β-Actin as a 
loading control. A 
representative autoradiograph 
from one of two independent 
experiments is shown.  
C. ANBL-6/WT myeloma cell 
which has higher level of 
MUC20 expression harboring 
either a control shRNA not 
targeting a known genomic 
sequence (con-shRNA), or 
shRNA suppressing MUC20 
(MUC20-shRNA), were 
exposed to the vehicle, or 
different concentration of 
either bortezomib (BTZ)(left 
panels) or carfilzomib 
(CFZ)(right panels) for 48 
hours. Their viability was 
evaluated using WST-1 
reagent. (* p < 0.05, # p < 0.01 
vs. ANBL-6/WT con-shRNA). 
D. ANBL-6/CR myeloma cell 
which has lower expression of 
MUC20 were infected with 
Lentiviral vectors without a 
cDNA insert (OE-con), or the cDNA for MUC20 (OE-MUC20). The viability to BTZ (left panels) 
or CFZ (right panels) for 48 hours were detected by WST-1. (* p < 0.05, # p < 0.01 vs. ANBL-
6/CR OE-con). 


 
 
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Figure 2. MET signaling 
pathways may regulate 
the PIs sensitivity  
A. Cell viability of KAS-6/1 
(left panel) and OPM-2 
(right panel) both WT and 
CR cells to CFZ with or 
without XL-184  as a c-Met 
inhibitor for 48h were 
detected by using WST1. 
(# p < 0.05 vs. CFZ single 
treatment group ). 
 
B. Cell viability of KAS-6/1 
(left panel) and ANBL-6 
(right panel) both WT and 
CR cells to CFZ with or 
without INCB28060 as a c-
Met inhibitor for 48h were 
detected by using WST1.     
(# p < 0.05 vs. CFZ single 
treatment group ). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Figure 3. Influence of MUC20 
expression on outcomes of patients 
treated with bortezomib 
A. Response rate of patient    
B. The progression-free survival (PFS) for 
patients with lower MUC20 expression 
levels (blue curves) or higher expression 
levels (red curves) were determined from 
Millennium Pharmaceuticals GEP 
database . All of the curves were plotted 
using Kaplan-Meier analyses, and 
significance was compared with the log 
rank test.  
C. OS of patient analyzed in the same 
manner, high (red) vs. low (blue) MUC20 
expression.     
 
 
 


 
 
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2.5 
CORRELATIVE STUDIES BACKGROUND 
 
We have briefly introduced above that POMP has an important role at the later steps of 
proteasome assembly and maturation. We indeed found the significantly higher expression of 
POMP protein in both bortezomib and carfilzomib resistant myeloma cells compared to wild to 
type cell lines. Further activation of c-Met by knock down of MUC20 lead to increasing of POMP 
and enhanced proteasome CT-L catalytic activity, while inhibition of c-Met signaling with ARQ-
197 or over expression of MUC20 lead to the decrease. These data suggest the c-Met signaling 
regulates POMP expression which in turn affects the proteasome catalytic activity, resulting in PIs 
resistance. ETS-Like Gene 1 (ELK1) was further identified as a target for ERK-1/2 which binds to 
the POMP promoter region, regulating its expression. Taken together, our data support a role for 
signaling through the MUC20/c-MET/ERK-1/2/ELK1/POMP axis in enhancing proteasome 
assembly and capacity, thereby reducing sensitivity to proteasome inhibitors like carfilzomib or 
bortezomib in myeloma. Our research also identified a new pathway that involved in PIs 
resistance and may provide a target for the treatment. 
 
These findings together support our central clinical hypothesis, that targeting the MUC20/c-
MET/ERK-1/2/ELK1/POMP signaling axis with the c-Met inhibitor cabozantinib will be an active 
approach for patients with RR MM who have developed PI resistance to carfilzomib.  Also, they 
support our central correlative hypotheses, which propose 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 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. 
 
 


 
 
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3. 
ELIGIBILITY 
 
3.1 
Inclusion Criteria   
 
1. Patients must have been previously diagnosed with histologically or cytologically confirmed 
symptomatic multiple myeloma, which require the presence of all three of the following 
International Myeloma Working Group 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) 
o Hypercalcemia (corrected calcium > 2.75 mmol/L or 11.5 mg/dL); OR 
o Renal insufficiency attributable to myeloma (serum creatinine >1.9 mg/dL); OR 
o Anemia; normochromic, normocytic with a hemoglobin value ≥2 g/dL below the 
lower limit of normal, or a hemoglobin or <10 g/dL; OR 
o Bone lytic lesions (MRI, CT or PET/CT with > 1 focal lesions ≥5 mm in size), 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, as defined by at least one of the following: 
 Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease 
 Monoclonal 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, along with an abnormal free light chain ratio 
 
3. Patients prior lines of therapy must be separated by the 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. 
 
4. Patients eligible for this trial will be those who have previously failed carfilzomib at any point 
either as a single agent, or carfilzomib in combination with dexamethasone, or carfilzomib in 
combination with dexamethasone and any of the following agents: revlimid, cyclophosphamide, 
pomalidomide, daratumumab or bendamustine. Given the potential for compounding/worsening 
toxicities with the addition of cabozantinib to carfilzomib, patients eligible for the trial will 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 (PD) 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 


 
 
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 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 multiple myeloma in 
the following timeframes: 
 Chemotherapy, biological therapy, immunotherapy, monoclonal antibody 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, at least 6 weeks prior to starting 
cabozantinib 
 Autologous stem cell transplantation or autologous chimeric antigen receptor (CAR) T cell 
therapy at least 12 weeks prior to starting cabozantinib 
 Allogeneic stem cell transplantation or allogeneic CAR T cell 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 Nebraska), because no dosing or adverse event data 
are currently available on the use of cabozantinib in patients <19 years of age.  
 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; please see 
Appendix E) 
 
9. Patients must have evidence of adequate bone marrow reserves, as defined by the following: 
 Absolute neutrophil count (ANC) ≥1,000 cells/mm3 without growth factors within 1 week of 
the initiation of treatment 
 Total white blood cell count (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 platelets ≥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 (SGOT) and ALT (SGPT) ≤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 


 
 
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 Creatinine clearance (CrCl) ≥30 mL/min., as measured by a 24-hour urine collection, or 
estimated by the Cockcroft and Gault formula: 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
 
72 x serum creatinine in mg/dL 
Male CrCl = (140 - age in years) x weight in kg x 1.00 
 
72 x serum creatinine in mg/dL 
 
Worsening urinary paraproteinemia will be considered in the context of IMWG disease 
response criteria on a monthly basis. 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 New York Heart Association (NYHA) class II, III, or IV congestive heart failure 
(please see Appendix F for the NYHA classification system) 
 Absence of uncontrolled angina or hypertension defined as sustained blood pressure (BP) 
> 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: 
o myocardial infarction; 
o unstable angina pectoris; 
o clinically-significant cardiac arrhythmias;  
o stroke (including transient ischemic attack (TIA), or other ischemic event);  
o thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a 
venous filter (eg, vena cava filter) are not eligible for this study)  
 Absence of clinically significant bradycardia, or other uncontrolled cardiac arrhythmia 
defined as grade 3 or 4 according to National Cancer Institute (NCI) Common Terminology  
 Absence of history of congenital long QT syndrome 
 
13. Patients who have received radiation therapy must have completed this at least 4 weeks prior 
to starting therapy with cabozantinib, with the following exceptions: 
 Local radiation therapy to enhance bone healing of a pathologic fracture may have been 
performed, as long as it was completed at least 2 weeks prior to starting cabozantinib 
 Local radiation therapy to treat post-fracture pain that is refractory to analgesics may have 
been performed, as long as it was completed at least 2 weeks prior to starting cabozantinib 
 
14. Patients who have undergone any recent major surgery must have done so at least 4 weeks 
prior to starting therapy with cabozantinib, with the following exceptions: 
 Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week prior 
to starting cabozantinib 
 Planned elective surgery unrelated to the patient’s diagnosis of multiple myeloma, such 
as hernia repair, may be allowed, at the discretion of the principle investigator, as long as 
it was performed at least 2 weeks prior to starting cabozantinib, and patients have 
recovered fully from this procedure 
 
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 cubic millimeter of blood, will be eligible. However, HIV positive patients on 
combination antiretroviral therapy will be ineligible, because of the potential for pharmacokinetic 
interactions with cabozantinib. 
 


 
 
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16. Screen subjects prior to treatment whose baseline hepatitis B serologic status is 
unknown.  Subjects, who are chronic carriers of hepatitis B virus, please screen with 
hepatitis B DNA to exclude active viral replication and monitor hepatitis B DNA at regular 
intervals while on study.  
 
 
17. 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). Male 
subjects must agree to not donate sperm for at least 90 days after the last dose of 
Carfilzomib.   
 
18. 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 (βHCG) or urine pregnancy test before receiving the first dose of 
cabozantinib 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. Women of reproductive potential will be counseled to use effective contraceptive 
measures to prevent pregnancy during treatment with either cabozantinib or carfilzomib. Patients 
shall be advised not to take cabozantinib or carfilzomib treatment while pregnant or breastfeeding. 
If a patient wishes to restart breastfeeding after treatment, she will be advised to discuss the 
appropriate timing with her physician. 
 
19. 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. 
 
3.2 
EXCLUSION CRITERIA 
 
1. Patients who are receiving any concurrent investigational agent with known or suspected 
activity against multiple myeloma, or those whose adverse events due to agents administered 
more than 4 weeks earlier have not recovered to a severity of grade 0 or grade 1. 
 
2. Patients who have known central nervous system involvement with multiple myeloma will 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. 
 
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. Cabozantinib is metabolized by CYP3A4. The metabolism and consequently overall 
pharmacokinetics of cabozantinib could be altered by inhibitors and/or inducers or other 
substrates of CYP3A4. It is recommended that chronic concomitant treatment with strong 


 
 
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CYP3A4 inhibitors (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, 
and St. John’s Wort) or inducers 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 enrolment. While 
mild inhibitors/inducers of these cytochrome P450 isoenzymes are not specifically excluded, 
investigators should be aware that cabozantinib exposure may be altered by the concomitant 
administration of these drugs, and avoidance is also recommended. Lists including medications 
and substances known or with the potential to interact with CYP3A4 are provided in Appendix G. 
 
 
6. Uncontrolled or ongoing/active infection. Due to side effect profile of cabozantinib, patients with 
the following history will also not be eligible for the trial: patients with a recent history of 
hemorrhage or hemoptysis; patients with dehiscence or wound healing complications requiring 
medical intervention; patients with severe hypertension that cannot be controlled (blood pressure 
of > 150 systolic or > 100 diastolic mmHg) with anti-hypertensive therapy within 7 days of first 
dose of therapy. 
 
7. Pregnant or lactating women are excluded from this study because cabozantinib is a tyrosine 
kinase inhibitor 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 cabozantinib, breastfeeding should be discontinued if the mother is treated with 
cabozantinib. 
 
8. Patients with non-secretory multiple myeloma, active plasma cell leukemia, defined as either 
having 20% of peripheral white blood cells comprised of CD138+ plasma cells, or an absolute 
plasma cell count of 2 x 109/L, known amyloidosis, or known POEMS syndrome (plasma cell 
dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes) 
 
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, due to the difficulty that would be faced in assessing the attribution of any events of 
hepatic toxicity while on cabozantinib therapy. 
 
11. Patients with a “currently active” second malignancy, other than non-melanoma skin cancer 
and carcinoma in situ of the cervix, should not be enrolled.  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.  In addition, 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 will be eligible.  Finally, patients who are on hormonal therapy 
for a history of either prostate cancer or breast cancer may enroll, if there has been no evidence 
of disease progression during the previous three 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 


 
 
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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: 
o 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 
o Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess 
within 6 months before  randomization, 
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to 
randomization 
 hemoptysis of ≥ 0.5 teaspoon (2.5ml) 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. 
 Patient who have developed or have had history of pulmonary hemorrhage while on 
carfilzomib will be excluded (fatal pulmonary hemorrhage has been observed with 
carfilzomib).  
 
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.  Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 14 days before first dose of study treatment Note: If a 
single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at 
intervals of approximately 3 min must be performed within 30 min after the initial ECG, 
and the average of these three consecutive results for QTcF will be used to determine 
eligibility.  
 
19.  Inability to swallow intact tablets 
 
20. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 × 
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);  
 
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 
1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted if started > 6 
months prior to randomization. LMWH used as therapeutic anticoagulation may increase observed 
PTT levels in subjects.  Anticoagulation with therapeutic doses of LMWH is allowed in subjects 
without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 


 
 
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24 weeks before randomization, and who have had no complications from a thromboembolic 
event or the anticoagulation regimen. 
 
22. Subjects who have Carfilzomib-related posterior reversible encephalopathy syndrome 
(PRES) and thrombotic microangiopathy (TMA) should not be challenged with Carfilzomib.   
 
3.3 
INCLUSION OF WOMEN AND MINORITIES 
 
Both men and women of all races and ethnic groups are eligible for this trial.  Accrual targets for 
men and women, as well as for various ethnic categories, are up to 32 subjects to obtain 17 
evaluable subjects. 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 Recruitment 
Subjects who are referred to the Nebraska Medical Center (NMC) / UNMC, or other IRB 
approved participating sites (MD Anderson), with relapsed and refractory (RR) multiple 
myeloma (MM) who have lost response to carfilzomib may be eligible for this study. 
 
Screening eligibility based on standard clinical care will be performed by the treating physician 
at the time of encounter. On initial presentation assessment of ECOG performance Status will 
be completed.  
 
After offering consent, the patient’s primary Oncologist will make the decision as to screened 
eligibility of the candidate based on the eligibility criteria listed above. If the patient is screened 
as potentially eligible, he/she will then be offered the option to participate. An informed consent 
will be signed by the patient after thorough review of the study is completed by the physician 
and his/her designee.  
 
Some insurance carrier’s may decline to cover the costs of usual medical care if the patient is 
participating in a clinical trial. The patient will be provided assistance by the research nurse 
coordinator or designated staff in determining if the insurance carrier will decline coverage. 
Insurance carriers may or may not pay for study related expenses. The patient can then decide 
if they wish to participate.  
 
4.2  
Eligibility Verification/Registration:  
 
Before patients are registered to the study, an eligibility checklist (Appendix A) must be 
completed to verify the subject meets the eligibility criteria.  Informed consent must be obtained 
by following procedures defined in section 12.6 entitled Process of Informed Consent.   
 
Subjects will be registered through the sponsor PI by contacting the UNMC Fred & Pamela 
Buffett Cancer Center Research Project Coordinator.  
 
All Study personnel from UNMC and non-UNMC IRB approved sites will contact the UNMC 
Research Project Coordinator if a patient appears to meet the eligibility criteria. They will email 
or fax the completed eligibility checklist (Appendix A). The Eligibility Check list will be 


 
 
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maintained in a study file. If the UNMC Multi-site Project Manager confirms that the subject 
meets criteria and target accrual has not been met, approval for the subject will be given. A 
confirmation of Registration will be forwarded by the UNMC Multi-site Project Manager. 
 
In the event of an after-hours potential enrollment (i.e., clinic coast time differences), or an 
immediate need-to-treat based on potential subject condition, registration can be accomplished 
by contacting the sponsor PI Dr. Muhamed Baljevic, MD directly by email: 
muhamed.baljevic@unmc.edu (response required) or by phone/pager 402-559-4000 or 402-
888-0345. Additionally, the UNMC Research Project Coordinator must be notified in or to meet 
UNMC Protocol Review Monitoring System (PRMS) reporting requirements. 
 
 
Participating/Collaborating Sites: 
Participating/Collaborating sites must have both local and UNMC IRB approval, and have met 
all other UNMC criteria to enroll. Study personnel from non-UNMC IRB approved sites will 
provide the UNMC Multi-site Project Manager with the following information: 
• 
Demographics fax/scan cover sheet (located in the Study Manual) 
• 
Copy of the signed and dated consent form (subject signature obliterated with 
signature line and subject  initials visible)  
• 
Signed Eligibility Checklist 
 
Registration Date: eligibility verification and notification of assigned subject number (by UNMC) 
will be known as the Registration date.  
 
Date of enrollment: is defined as the date of the start of study treatment / first protocol related 
intervention. 
 
The listed documents/ information for subjects enrolled will be provided to the PRMS office within 
one (1) week of enrollment as applicable: 
o UNMC and Participating Site Protocol Numbers  
o Investigator/Participating Site Identifier (ID)  
o Subject ID: Assigned by UNMC [Site ID followed by subject number (##-###)]  
o Consent Date: Date subject signed consent  
o Patient demographics: gender, birth date (mm/dd/yyyy), race, ethnicity 
o Re-consent Date: (If applicable)  
o Ineligibility Status: (If known)  
o Off Study Date: (If applicable)  
 
4.3  
Pathology Requirements 
Pathology material will be reviewed, and the diagnosis confirmed by each site’s Pathology 
department as outlined in protocol.   
 
Additional bone marrow aspirate pathology material is required to be captured at screening and 
after cycle 2 for correlative studies.  See Section 5.8 for details of the required samples. 
 
 
4.4   Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
 
If a subject does not receive any assigned protocol treatment after consenting, baseline and 


 
 
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follow-up data will still need to be collected and submitted according to the instructions in the 
protocol.  The reason he/she did not receive any treatment and the date and type of the first non-
protocol treatment that the subject receives must also be reported.  
 
4.5  
Requirements for Submitting Regulatory Documents UNMC and 
Participating Institutions:  
 
Before an institution may enroll patients, all site activation criteria must be met by submitting 
required protocol specific regulatory documents to the study project manager at UNMC Fred & 
Pamela Buffett Cancer Center. 
 
4.6  
Required Protocol Specific Regulatory Documents  
 
1. Confirmation that the UNMC Team Designee(s) conducted an initial site 
teleconference prior to opening a protocol to accrual at the participating site. 
2. Copy of IRB Informed Consent Document.  
 
NOTE: Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed consent document 
must be justified in writing by the investigator and approved by the IRB.  
3. Copy of each participating/collaborating site’s IRB Approval Letter and current IRB 
Roster, Federal Wide Assurance (FWA) Number or IRB Statement of Compliance. 
 
NOTE: The above submissions must include the following details:  
• Full protocol title and number  
• Version Date  
• Type of review (full board vs. expedited)  
• Date of review.  
• Signature of IRB official  
 
 
 
5. 
TREATMENT PLAN 
 
5.1  
AGENT ADMINISTRATION 
 
The recommended starting daily dose of cabozantinib is 20 mg (one 20-mg capsules). It will not 
be administered with food. Patients will be instructed not to eat for at least 2 hours before and at 
least 1 hour after taking cabozantinib. Capsules will be swallowed as whole and will not be 
opened. Patients will be instructed to not take a missed dose within 12 hours of the next dose. 
cabozantinib will not be ingested with grapefruit, grapefruit juice or nutritional supplements that 
are known to inhibit cytochrome P45. 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 9.  Appropriate dose modifications are described in Section 5.7.  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 


 
 
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To assess compliance with treatment, all patients will be requested to maintain a medication diary 
of each dose of medication.  This medication diary will be returned to the research staff at the end 
of each cycle of therapy.  A sample patient study medication diary is provided in Appendix H. 
 
5.1.1 Cabozantinib 
 
Cabozantinib tablets should be administered by mouth (PO) daily (one 20-mg capsules for the 
initial testing dose). Tablets should be taken with water and swallowed whole, and missed or 
vomited dose should not be replaced.  The patient should be instructed to take the next scheduled 
dose at the regularly scheduled time.  Patients will receive cabozantinib daily continuously during 
entire 28-day treatment cycle (Days 1-28 on therapy).  
 
Refer to Section 8.2.4 for further details on administrations of other study drugs, carfilzomib and 
dexamethasone.  
 
 
5.2 
PATIENT ASSESSMENTS 
 
5.2.1 SCREENING 
 
The screening period for the following assessments will be considered to be any time within the 
twenty eight days prior to day 1 of study-directed treatment: 
 A comprehensive history, including a description of prior anti-neoplastic treatment 
regimens, and current use of supportive therapies as well as concomitant medications 
 A comprehensive physical examination including vital sign measurements (systolic and 
diastolic blood pressure, respiratory rate, pulse, temperature) along with height and weight  
 ECOG performance status determination 
12-lead electrocardiogram  Note: If a single ECG shows a QTcF with an absolute value 
> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed 
within 30 min after the initial ECG, and the average of these three consecutive results for 
QTcF will be used to determine eligibility.  
 Echocardiogram (TTE) 
 Postero-anterior and lateral chest radiography 
 Myeloma skeletal/bony survey to document lytic disease 
 Computed tomography or magnetic resonance to evaluate the size and location of 
plasmacytomas, if clinically indicated by standard of care(SOC) 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, platelet count) 
o CD4+ cell count in patients with known HIV-seropositivity 
o Hepatitis B serology status, if unknown 
o Serum chemistry (creatinine, blood urea nitrogen (BUN), uric acid, total bilirubin, 
aspartate aminotransferase (AST (SGOT)), alanine aminotransferase (ALT 
(SGPT)), alkaline phosphatase, lactate dehydrogenase (LDH), sodium, potassium, 
chloride, bicarbonate, magnesium, glucose, calcium, phosphorous, total protein 
and albumin) 
o Serum β-HCG or urine pregnancy test for women of child-bearing potential 
o Coagulation parameters, including prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) 
o Serum β-2-microglobulin 


 
 
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 Evaluation of serum and/or urine parameters of measurable disease, including serum 
protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free κ 
and λ light chain concentrations as well as the κ/λ ratio, and a 24-hour urine collection for 
total volume with total protein and electrophoresis with immunofixation for Bence Jones 
proteinuria 
 Bone marrow aspiration and biopsy, with samples obtained for hematopathology review, 
flow cytometry, cytogenetic studies by routine karyotyping and fluorescence in situ 
hybridization (FISH; including probes for del 13q14, t(4,14), t(14,16), t(14,20) and del 17p), 
and correlative studies.  
 Serum sample for evaluation of baseline MUC20 level 
 An oral examination will be performed prior to initiation of cabozantinib and periodically 
during therapy, and patients advised regarding good oral hygiene practices. 
o Note: the oral examination can be completed as part of an ENT referral visit 
 
 
 
5.2.2 CYCLE 1 ASSESSMENTS 
 
Prior to initiation of any study-directed therapy, the following assessments will be performed 
within three days of day 1 of cycle 1 to confirm the patient’s eligibility: 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, red blood cell count, platelet count) 
o Serum chemistry (creatinine, BUN, uric acid, total bilirubin, AST, ALT, alkaline 
phosphatase, LDH, sodium, potassium, chloride, bicarbonate, magnesium, 
glucose, calcium, phosphorous, total protein and albumin) 
o Serum β-HCG or urine pregnancy test for women of child-bearing potential 
o PT and aPTT 
 Evaluation of serum and/or urine parameters of measurable disease, including serum 
protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free κ 
and λ light chain concentrations as well as the κ/λ ratio, and a 24-hour urine collection for 
total volume with total protein and electrophoresis with immunofixation for Bence Jones 
proteinuria.  Please note that these tests should not be repeated if they were performed 
within fourteen days during the screening period. 
 Urine protein should be monitored regularly during treatment and treatment discontinued 
in patients who develop nephrotic syndrome. 
 
In addition, prior to initiation of any study-directed therapy, the following assessments will be 
performed on day 1 of cycle 1 to confirm the patient’s eligibility: 
 An abbreviated interval medical history, including a description of current supportive 
therapies as well as concomitant medications 
 An 
abbreviated, 
symptom-directed 
physical 
examination 
including 
vital 
sign 
measurements (systolic and diastolic blood pressure, respiratory rate, pulse, temperature) 
along with weight 
 Any additional studies that the physician, physician assistant, nurse practitioner, or 
research nurse feels are medically appropriate 
 ECOG performance status determination 
 Electrocardiography (ECG) will be performed  
 Measurement of symptom burden using the MDASI-MM tool (Appendix B) 


 
 
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 Determination of the quality of life using the QLQ-C30 (Appendix C) and QLQ - MY20 
(please see Appendix D) tools 
 The patient will be provided with a study medication diary for cycle 1 that will allow them 
to document compliance with the treatment schedule (please see Appendix H for a sample 
patient study medication diary) 
 
Once cabozantinib has been initiated in cycle 1, the patient will return on days 8 and 22 (± 3 
day) for the following assessments: 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, red blood cell count, platelet count) 
 
Once cabozantinib has been initiated in cycle 1, the patient will return on day 15 (± 3 days) for 
the following assessments: 
 An abbreviated interval medical history, including a description of current supportive 
therapies as well as concomitant medications, and an evaluation of any possible toxicities 
due to therapy and their severity 
 An 
abbreviated, 
symptom-directed 
physical 
examination 
including 
vital 
sign 
measurements (systolic and diastolic blood pressure, respiratory rate, pulse, temperature) 
 Any additional studies that the physician, physician assistant, nurse practitioner, or 
research nurse feels are medically appropriate 
 ECOG performance status determination  
 Measurement of symptom burden using the MDASI-MM tool 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, red blood cell count, platelet count) 
o Serum chemistry (creatinine, BUN, uric acid, total bilirubin, AST, ALT, alkaline 
phosphatase, LDH, sodium, potassium, chloride, bicarbonate, magnesium, 
glucose, calcium, phosphorous, total protein and albumin) 
 
5.2.3 CYCLE 2 ASSESSMENTS 
 
Prior to continuing further therapy with cabozantinib in cycle 2, the following assessments will be 
performed within three days of day 1 of the cycle: 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, red blood cell count, platelet count) 
o Serum chemistry (creatinine, BUN, uric acid, total bilirubin, AST, ALT, alkaline 
phosphatase, LDH, sodium, potassium, chloride, bicarbonate, magnesium, 
glucose, calcium, phosphorous, total protein and albumin) 
o Serum β-HCG or urine pregnancy test for women of child-bearing potential 
 
 Any additional studies that the physician, physician assistant, nurse practitioner, or 
research nurse feels are medically appropriate 
 Evaluation of serum and/or urine parameters of measurable disease, including serum 
protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free κ 
and λ light chain concentrations as well as the κ/λ ratio, and a 24-hour urine collection for 
total volume with total protein and electrophoresis with immunofixation for Bence Jones 
proteinuria.  Please note that these data will be collected after cycle 1 to evaluate the 
kinetics of any responses to cabozantinib, but patients will be treated for a total of two full 


 
 
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cycles before a formal assessment of disease response is made.  Subsequent disease 
response assessments will be made with every cycle (i.e. after cycle 3, 4, 5, etc.). 
 
In addition, prior to continuation of any study-directed therapy, the following assessments 
will be performed on day 1 of each cycle: 
 An abbreviated interval medical history, including a description of current supportive 
therapies as well as concomitant medications, and an evaluation of any possible toxicities 
due to therapy and their severity 
 An 
abbreviated, 
symptom-directed 
physical 
examination 
including 
vital 
sign 
measurements (systolic and diastolic blood pressure, respiratory rate, pulse, temperature) 
along with weight 
 ECOG performance status determination 
 Electrocardiography (ECG) will be performed in patients to monitor QTcF 
 Measurement of symptom burden using the MDASI-MM tool 
 Determination of the quality of life using the QLQ-C30 and QLQ – MY20 tools 
 Collection of the study medication diary for the previous cycle of therapy from the patient 
to document treatment compliance 
 
In addition, the following assessments will be performed on day 15 of each cycle (± 3 days): 
 Measurement of symptom burden using the MDASI-MM tool (Appendix B) 
 
 
5.2.4 ASSESSMENTS DURING TREATMENT CYCLE 3 AND LATER 
 
Prior to continuing further therapy with cabozantinib in cycle 3, and in all subsequent 
cycles of therapy, the following assessments will be performed within three days of day 
1 of the cycle: 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, red blood cell count, platelet count) 
o Serum chemistry (creatinine, BUN, uric acid, total bilirubin, AST, ALT, alkaline 
phosphatase, LDH, sodium, potassium, chloride, bicarbonate, magnesium, 
glucose, calcium, phosphorous, total protein and albumin) 
o Serum β-HCG or urine pregnancy test for women of child-bearing potential 
 
 Serum sample for evaluation of MUC20 level (prior to start of cycle 3 only) 
 Any additional studies that the physician, physician assistant, nurse practitioner, or 
research nurse feels are medically appropriate 
 Evaluation of serum and/or urine parameters of measurable disease, including serum 
protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free κ 
and λ light chain concentrations as well as the κ/λ ratio, and a 24-hour urine collection for 
total volume with total protein and electrophoresis with immunofixation for Bence Jones 
proteinuria.  Please note that these data will be collected after cycle 1 to evaluate the 
kinetics of any responses to cabozantinib, but patients will be treated for a total of two full 
cycles before a formal assessment of disease response is made.  Subsequent disease 
response assessments will be made with every cycle (i.e. after cycle 3, 4, 5, etc.). 
 Bone marrow aspiration and biopsy will be performed to confirm a possible complete 
remission, with samples obtained for hematopathology review, flow cytometry, cytogenetic 
studies by routine karyotyping and FISH, including probes for del 13q14, t(4,14), t(14,16), 
and del 17p, and correlative studies (performed once only at cycle 3). 


 
 
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In addition, prior to continuation of any study-directed therapy, the following assessments will be 
performed on day 1 of each cycle: 
 An evaluation of disease response to determine eligibility to continue therapy will be 
performed after the first two cycles, and then every cycle after that.  Patients with evidence 
of disease progression after cycle 2 or later, which is confirmed according to the Uniform 
criteria, will be removed from the study at the time of confirmation of disease progression 
is obtained. 
 An abbreviated interval medical history, including a description of current supportive 
therapies as well as concomitant medications, and an evaluation of any possible toxicities 
due to therapy and their severity 
 An 
abbreviated, 
symptom-directed 
physical 
examination 
including 
vital 
sign 
measurements (systolic and diastolic blood pressure, respiratory rate, pulse, temperature) 
along with weight 
 ECOG performance status determination 
 Electrocardiography (ECG) will be performed every 12 weeks 
 Measurement of symptom burden using the MDASI-MM tool 
 Determination of the quality of life using the QLQ-C30 and QLQ – MY20 tools 
 Collection of the study medication diary for the previous cycle of therapy from the patient 
to document treatment compliance 
 
In addition, the following assessments will be performed on day 15 of each cycle (± 3 days): 
 Measurement of symptom burden using the MDASI-MM tool 
 
 
 
5.2.5 END OF STUDY ASSESSMENT 
 
Patients who will be discontinuing therapy with cabozantinib due to any of the circumstances 
detailed in Section 5.4 will have an end-of-study assessment.  This will occur within thirty days 
of discontinuing therapy, and will include: 
 An comprehensive interval medical history, including a description of current supportive 
therapies as well as concomitant medications, and an evaluation of any possible 
remaining toxicities due to therapy and their severity 
 An comprehensive physical examination including vital sign measurements (systolic and 
diastolic blood pressure, respiratory rate, pulse, temperature) along with weight 
 ECOG performance status determination 
 12-lead ECG 
 Measurement of symptom burden using the MDASI-MM tool 
 Determination of the quality of life using the QLQ-C30 and QLQ-MY20 tools 
 Samples for clinical laboratory evaluations as follows: 
o Hematology (white blood cell count with automated differential, hemoglobin, 
hematocrit, red blood cell count, platelet count) 
o Serum chemistry (creatinine, BUN, uric acid, total bilirubin, AST, ALT, alkaline 
phosphatase, LDH, sodium, potassium, chloride, bicarbonate, magnesium, 
glucose, calcium, phosphorous, total protein and albumin) 
o Serum β-HCG or urine pregnancy test for women of child-bearing potential 
 Any additional studies that the physician, physician assistant, nurse practitioner, or 
research nurse feels are medically appropriate 
 Evaluation of serum and/or urine parameters of measurable disease, including serum 
protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free κ 


 
 
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and λ light chain concentrations as well as the κ/λ ratio, and a 24-hour urine collection for 
total volume with total protein and electrophoresis with immunofixation for Bence Jones 
proteinuria 
 
5.2.6 DATA COLLECTED AFTER THE END OF STUDY ASSESSMENT 
 
To evaluate the impact of therapy with cabozantinib and carfilzomib for RR MM on the ability to 
harvest stem cells in any patients who go on to undergo subsequent stem cell mobilization, pilot 
data will be collected about the mobilization regimen used, the number of stem cells collected, 
and the number of days of apheresis necessary.  In addition, in those patients who proceed to 
stem cell transplantation, data will be collected about the kinetics of stem cell engraftment, 
including the number of days to neutrophil and platelet recovery. 
 
5.3  
CONCOMITANT MEDICATION  
 
 
5.3.1 Anticancer Therapy 
 
Local intervention is discouraged unless medically unavoidable. Subjects receiving local 
intervention (eg, palliative radiation) are allowed to continue to receive study treatment at the 
investigator’s discretion. 
 
5.3.2 Other Medications 
 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before the first dose of study treatment through 30 days after the date of 
the last dose of study treatment are to be recorded in the case report forms. 
5.3.3 PERMITTED CONCOMITANT MEDICATIONS 
 
Standard Therapies 
 
Standard therapies for concurrent medical conditions are allowed, except for the use of 
corticosteroids beyond the limits allowed in the inclusion and exclusion criteria (Sections 3.1 and 
3.2).  Transfusions, hormone replacement, and short term higher doses of corticosteroids should 
be utilized as indicated by standard clinical practice 
 
Erythropoiesis Stimulating Agents (ESA) 
 
Please follow ASCO or MEDICARE guidelines for the use of ESA in patients diagnosed with 
cancer, drug labels and the Food and Drug Administration (FDA) alerts dated March 9, 2007; 
November 8, 2007; March 12, 2008; July 31, 2008; and December 2, 2008.   
 
Hematopoietic growth factors 
 
Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, American Society of Clinical Oncology [ASCO] or [European Society for Medical 
Oncology] ESMO guidelines) 
 
Antiemetics and Antidiarrheal 


 
 
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Prophylactic and supportive antiemetics and antidiarrheal medications may be administered 
according to standard clinical practice if clinically indicated. 
 
Bisphosphonates 
 
Drugs used to control bone loss (eg, bisphosphonates and denosumab) are allowed if started 
before screening activities but may not be initiated or exchanged during the course of the study 
and require Sponsor approval.  
 
Thromboembolism Prophylaxis: 
Because cabozantinib treatment results in an increased incidence of thrombotic events (venous 
thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in cabozantinib-treated 
and placebo-treated patients, respectively), patients will be on prophylactic dose of Aspirin while 
on therapy (ASA 81-325 mg PO daily). If patients are on a greater dose of Aspirin for other 
medical reasons, that dose of Aspirin will be continued.  
 
• 
Individualized anticoagulation therapy with heparin is allowed if it can be provided safely and 
effectively under the following circumstances:  
o Low dose heparins for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion.  
o Therapeutic doses of low molecular weight heparins (LMWH) at the time of first dose 
are allowed if the subject has no evidence of brain metastasis, has been on a stable 
dose of LMWH for at least 12 weeks, and has had no complications from a 
thromboembolic event or the anticoagulation regimen.  
o Therapeutic doses of low molecular weight heparins (LMWH) after first dose are 
allowed if clinically indicated (eg, for the treatment of deep venous thrombosis), and 
the benefit outweighs the risk per the investigator’s discretion. For management of 
thromboembolic complications while on study, refer to Section 5.7 
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (eg, due to kidney dysfunction);  
For restrictions on oral anticoagulants see Section 5.3.4. 
 
Gastric pH  modifying agents 
 
Administration of the PPI esomeprazole resulted in no clinically-relevant effect on cabozantinib 
plasma PK in healthy volunteers (Study XL184-018). Therefore, concomitant use of gastric pH 
modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) is not contraindicated in 
subjects administered cabozantinib.  Cimetidine should be avoided due to potential CYP 
interactions 
 
5.3.4 CONCOMITANT MEDICATIONS TO AVOID IF POSSIBLE 
The following therapies should be avoided if possible, while the subject is on study: 


 
 
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• 
Palliative external radiation to bone metastasis for bone pain should not be performed while 
on study. Subjects who have such an intervention may be considered not evaluable (and 
may be assigned a censoring or progression date) for certain efficacy endpoints; 
• 
Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg,  phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended; 
• 
Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, because this 
could significantly increase the exposure to cabozantinib; 
• 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations and should be avoided. Grapefruit and 
Seville oranges may also increase plasma concentrations of cabozantinib and should be 
avoided. 
Additional information on potential drug interactions with cabozantinib is provided in Section 
5.3.5. 
 
5.3.5  Potential for Drug Interactions 
 
Cytochrome P450 (CYP): Data from a clinical drug interaction study (Study XL184-008) show 
that clinically relevant steady-state concentrations of cabozantinib appear to have no marked 
effect on the area under the plasma drug concentration time curve (AUC) of co-administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit 
CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 
isozymes that have lower [I]/Ki values compared with CYP2C8 (ie, CYP2C9, CYP2C19, 
CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce 
cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib 
concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s 
Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong 
CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with 
caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 


 
 
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the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) 
may increase cabozantinib concentrations. Grapefruit and Seville oranges may also increase 
plasma concentrations of cabozantinib and should be avoided. Strong CYP3A4 inhibitors should 
be avoided and other drugs that inhibit CYP3A4 should be used with caution because these 
drugs have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended.  
In addition, cimetidine should be avoided because of its potential to interfere with CYP3A4 
mediated metabolism of cabozantinib. 
Please refer to Section 8.1.5 of the protocol for more information. 
 
 
5.4  
DURATION OF THERAPY 
 
In the absence of treatment delays due to adverse event(s), treatment may continue without a 
limitation on the number of cycles, unless one of the following criteria applies: 
 Disease progression after two cycles or later of therapy 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 Patient becomes pregnant 
 Patient loses the ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of a psychiatric or physical illness 
 Patient achieves complete remission (CR), and the patient and investigator feel that 
discontinuation of cabozantinib is in the patient’s best interests, or 
 Patient achieves a level of response that qualifies him or her for another therapy for 
which they provide consent, such as high dose therapy with autologous stem cell 
transplantation. 
 
 
5.5       DURATION OF FOLLOW-UP 
 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
 
5.6  
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
5.7. 
DOSING DELAYS / DOSE MODIFICATIONS 
 


 
 
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In Phase I of this study we will determine the MTD among three doses. DLTs will be based 
solely on adverse events that occur during cycle 1.  The definition of DLT includes: 
a. Any non-hematological toxicity Grade ≥ 3, except for alopecia and nausea uncontrolled by 
medical management. 
b. Grade 4 neutropenia lasting more than 5 days. 
c. Febrile neutropenia of any duration (ANC <1.0 x 109/L fever ≥ 38.5°C) 
d. Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding, or any 
requirement for platelet transfusion 
e. Grade 4 anemia, unexplained by underlying disease. 
 
We will study three dose levels using the 3+3 algorithm, so that we will accrue a minimum of 3 
patients and a maximum of 18 patients in Phase I. 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.  In the 
event that dose modifications are needed for toxicities, the following additional dose levels will 
be used: 
 
Dose Level 
Cabozantinib Dose 
-1 
20 mg p.o., daily 
0 
40 mg p.o., daily 
+1 
60 mg p.o., daily 
 
 
 
To allow for optimal experimental design, capped dose of carfilzomib of 27 mg/m2 will be used in 
the 
study 
without 
dose 
escalations 
or 
de-escalations. 
Given 
the 
potential 
for 
compounding/worsening toxicities with the addition of cabozantinib to carfilzomib, patients eligible 
for the trial will have to have had very good tolerance to carfilzomib in the context of treatment 
regimens they were receiving, with resolved prior carfilzomib toxicities to grade 1 or better, and 
no toxicities due to carfilzomib that required dose reductions to less than 27 mg/m2 as dose 
adjustments will be allowed in the carbozantinib only. Stopping of carfilzomib however will be 
allowed if the adverse events secondary to carfilzomib that require its stopping are observed/met.  
 
Specific dose modifications guidelines will be followed for the adverse events nausea, vomiting, 
diarrhea, neutropenia, and thrombocytopenia, and are detailed below.  If a patient experiences 
several adverse events and there are conflicting recommendations, the investigator should use 
the recommended dose adjustment that reduces the dose to the lowest level.     
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose for Cabozantinib 
≤Grade 1 
No change in dose 
Grade 2 
Hold until ≤Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until <Grade 2.  Resume at one dose level lower, if 
indicated.** 
Grade 4 
Off protocol therapy 


 
 
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5.7.1 PRECAUTIONS, WARNINGS, AND OTHER SUPPORTIVE CARE GUIDELINES  
 
Gastrointestinal Disorders  
The most common non-hepatobiliary GI AEs reported in clinical studies with cabozantinib 
regardless of causality are diarrhea, nausea, decreased appetite, vomiting, constipation, 
stomatitis and abdominal pain.  
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: Loperamide anti-diarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion 
until diarrhea-free for 12 hours (maximum dosage: 16 mg/24 hours). 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose for Cabozantinib 
≤Grade 1 
No change in dose 
Grade 2 
Hold until ≤Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until <Grade 2.  Resume at one dose level lower, if 
indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > one dose reductions should go off protocol therapy. 
Recommended management: Antiemetics. 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose for Cabozantinib 
≤Grade 1 
No change in dose 
Grade 2 
Hold until ≤Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until <Grade 2.  Resume at one dose level lower, if 
indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > one dose reductions should go off protocol therapy. 
Recommended management: Antiemetics. 


 
 
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Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 
antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial 
management. Some subjects may require concomitant treatment with more than one 
antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhea to 
tolerable levels, study treatment should be temporarily interrupted or dose reduced per above 
table. 
In addition, general supportive measures should be implemented including hydration, correction 
of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-containing 
products, high fat meals, and alcohol.  
Nausea and Vomiting 
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and 
vomiting or as prophylaxis to prevent emesis, along with supportive care in accordance to 
clinical practice guidelines. The 5-HT3 receptor antagonists are recommended over chronic use 
of NK-1 receptor antagonists and dexamethasone (NK-1 receptor antagonists can induce or 
inhibit CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower cabozantinib 
exposure (see Sections 5.3.5). Caution is also recommended with the use of nabilone, which is 
a weak inhibitor of CYP3A4. When therapy with antiemetic agents does not control the nausea 
or vomiting to tolerable levels, study treatment should be temporarily interrupted or dose 
reduced per the above table. 
Dehydration may be associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented. 
 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk for complications before study treatment is initiated. Appropriate correction of local 
factors should be instituted as indicated, such as modification of ill-fitting dentures and 
appropriate care of gingivitis.  
During treatment with cabozantinib good oral hygiene and standard local treatments such as 
nontraumatic cleansing and oral rinses (eg, with a weak solution of salt and baking soda) should 
be maintained. The oral cavity should be rinsed after meals, and dentures should be cleaned 
and brushed often to remove plaque. Local treatment should be instituted at the earliest onset of 
symptoms. Obtain bacterial/viral culture if oral infection is suspected and treat infection as 
indicated by local guidelines. When stomatitis interferes with adequate nutrition and local 
therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib 
should be considered per the table For other non-hematologic adverse events, and for 
hematologic adverse events, the following criteria for dose reduction should be used: 
 
Table 5-1: 
Recommended carfilzomib and cabozantinib dose modification plan for 
hematologic and non-hematologic toxicities. 
 
 
 


 
 
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Event Grade  
(NCI CTC V4.03) and Category 
Action by Agent 
Grade 
Adverse Event 
Carfilzomib 
Cabozantinib 
Grade 2 
Pulmonary 
Hypertension or 
Pulmonary 
Complications 
Withhold carfilzomib until 
resolved or returned to 
baseline. Restart at the dose 
used prior to the event or 
reduced dose (from 27 
mg/m2 to 20 mg/m2, OR from 
20 mg/m2 to 15 mg/m2), at 
the discretion of the 
physician. If tolerated, the 
reduced dose may be 
escalated to the previous 
dose at the discretion of the 
physician. 
Congestive heart 
failure or myocardial 
ischemia 
Withhold carfilzomib until 
resolved or returned to 
baseline. Restart at the dose 
used prior to the event or 
reduced dose (from 27 
mg/m2 to 20 mg/m2, OR from 
20 mg/m2 to 15 mg/m2), at 
the discretion of the 
physician. If tolerated, the 
reduced dose may be 
escalated to the previous 
dose at the discretion of the 
physician. 
Rash, or hand-foot 
syndrome only 
Withhold cabozantinib until 
recovery to Grade 1 or 
screening value. Administer 
cabozantinib at the next lower 
dose for subsequent cycles, 
unless further dose reduction 
is required.  If a second hold is 
required for the same event, 
administer cabozantinib at 
lower dose for subsequent 
cycles. 


 
 
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Event Grade  
(NCI CTC V4.03) and Category 
Action by Agent 
Grade 
Adverse Event 
Carfilzomib 
Cabozantinib 
Non-hematologic 
toxicities 
Continue current dose level. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 
Hematologic 
(neutropenia, 
thrombocytopenia, 
anemia) 
Withhold carfilzomib dose. 
If fully recovered before next 
scheduled dose, continue at 
same dose level. 
If recovered to Grade 2 
neutropenia or Grade 3 
thrombocytopenia, reduce 
dose by one dose level:  
from 27 mg/m2  to 20 mg/m2, 
OR from 20 mg/m2  to 15 
mg/m2. 
If tolerated, the reduced 
dose may be escalated to 
the previous dose at the 
discretion of the physician. 
TMA: 
If TMA is suspected, hold 
carfilzomib and manage per 
standard of care. If TMA is 
confirmed and related to 
carfilzomib, permanently 
discontinue carfilzomib. If 
TMA is excluded, may restart 
carfilzomib.  
Withhold cabozantinib. 
If the relevant lab value 
recovers to: 1.0×109/L for 
ANC, 8 g/dL for hemoglobin, or 
50×109/L for platelets, resume 
cabozantinib treatment at 
same dose level.  If the 
relevant lab value takes more 
than 3 weeks to recover to the 
level described above, restart 
cabozantinib administration at 
the next lower dose.  If a 
second hold is required for the 
same event, administer 
cabozantinib at the next lower 
dose for subsequent cycles 
(for those subjects starting at 
40 mg dose, cabozantinib 
would be discontinued is 
second hold required). 
Hepatic Toxicity 
25% dose reduction in case 
of baseline or treatment 
emergent mild or moderate 
hepatic impairment. Withhold 
carfilzomib until resolved or 
returned to baseline. After 
resolution, consider if 
restarting is appropriate. May 
be restarted at the dose 
(from 27 mg/m2 to 20 mg/m2, 
OR from 20 mg/m2 to 15 
mg/m2) with frequent 
monitoring of liver function. If 
tolerated, the reduced dose 
may be escalated to the 
previous dose at the 
discretion of the physician. 
Monitor liver enzymes 
regularly, regardless of 
baseline values, and modify 
dose based on toxicity.  


 
 
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Event Grade  
(NCI CTC V4.03) and Category 
Action by Agent 
Grade 
Adverse Event 
Carfilzomib 
Cabozantinib 
Renal 
Serum creatinine ≥2 times 
baseline, CrCl <15 
mL/minute or CrCl 
decreases to ≤50% of 
baseline, or patient requires 
dialysis: Withhold dose and 
monitor renal function. If 
renal toxicity is due to 
carfilzomib, resume dosing 
when renal function has 
improved to within 25% of 
baseline; resume with a 
reduced dose by 1 dose 
level. 
Cardiac Toxicity: 
Grade 3 or 4, new onset 
or worsening of: 
1. Congestive heart 
failure; 
2. Decreased left 
ventricular function 
3. Myocardial ischemia 
Withhold until resolved or 
returned to baseline. 
After resolution, consider if 
restarting carfilzomib at a 
reduced dose is appropriate 
(from 27 mg/m2 to 20 mg/m2, 
OR from 20 mg/m2  to  
15 mg/m2. 
If tolerated, the reduced 
dose may be escalated to 
the previous dose at the 
discretion of the physician. 
Peripheral Neuropathy 
Withhold until resolved or 
returned to baseline. 
After resolution, consider if 
restarting carfilzomib at a 
reduced dose is appropriate 
(from 27 mg/m2 to 20 mg/m2, 
OR from 20 mg/m2  to  
15 mg/m2. 
If tolerated, the reduced 
dose may be escalated to 
the previous dose at the 
discretion of the physician. 
Clinically significant 
Non-hematologic 
Withhold until resolved or 
returned to baseline. 
After resolution, consider if 
restarting carfilzomib at a 
reduced dose is appropriate 
(from 27 mg/m2 to 20 mg/m2, 
OR from 20 mg/m2  to  
15 mg/m2. 
If tolerated, the reduced 
dose may be escalated to 
the previous dose at the 
discretion of the physician. 
Withhold cabozantinib until 
recovery to Grade 1 or 
screening value.  
Administer cabozantinib at the 
next lower dose for 
subsequent cycles, unless 
further dose reduction is 
required.  If a second hold is 
required for the same event, 
administer cabozantinib at 
lower dose for subsequent 
cycles.  For those subjects 
starting at 40 mg dose, 
cabozantinib would be 


 
 
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Event Grade  
(NCI CTC V4.03) and Category 
Action by Agent 
Grade 
Adverse Event 
Carfilzomib 
Cabozantinib 
PRES: 
If PRES is suspected, hold 
carfilzomib. Consider 
evaluating with MRI for onset 
of symptoms suggestive of 
PRES. If PRES if confirmed, 
permanently discontinue 
carfilzomib. If PRES is 
excluded, may resume 
carfilzomib at same dose if 
clinically appropriate.  
discontinued if second hold 
required. 
Grade 4 
Non-hematologic 
(including hemorrhage 
and peripheral 
neuropathy) 
Withhold carfilzomib until 
resolved or returned to 
baseline.  
Consider restarting at the 
next scheduled treatment 
with one dose level reduction 
(from 27 mg/m2 to 20 mg/m2, 
OR from 20 mg/m2 to 15 
mg/m2). 
If tolerated, the reduced 
dose may be escalated to 
the previous 
dose at the discretion of the 
physician. 
Withhold cabozantinib until 
recovery to Grade 1 or 
screening value.  
Consult with the Medical 
Monitor or designee prior to 
restarting cabozantinib.  If the 
Investigator and Medical 
Monitor concur, administer 
cabozantinib at the next lower 
dose for subsequent cycles, 
unless further dose reduction 
is required.  If a second hold is 
required for the same event, 
administer cabozantinib at 
lower dose for subsequent 
cycles.  For those subjects 
starting at 40 mg dose, 
cabozantinib would be 
discontinued if second hold 
required. 
Hematologic 
(neutropenia, 
thrombocytopenia, 
anemia, febrile 
neutropenia) 
Hold drug. If fully recovered 
before next scheduled dose, 
continue carfilzomib at same 
dose level. If recovered to 
Grade 2 neutropenia or 
Grade 3 thrombocytopenia, 
reduce dose by one dose 
level (from 27 mg/m2 to 20 
mg/m2, OR from 20 mg/m2 to 
15 mg/m2).  If tolerated, the 
reduced dose may be 
escalated to the previous 
dose at the discretion of the 
physician. 
Withhold cabozantinib. 
If the relevant lab value 
recovers to: 1.0×109/L for 
ANC, 8 g/dL for hemoglobin, or 
50×109/L for platelets, resume 
treatment at next lower dose 
for subsequent cycles, unless 
further dose reduction is 
required. 
Permanently 
discontinue for  
any of the following 
1. Hypertensive crisis  
2. Hypertensive emergency 
3. Malignant hypertension 
1. Development of visceral 
perforation or fistula 
formation 
2. Severe hemorrhage 
3. Serious arterial 
thromboembolic event (e.g., 
myocardial infarction, 
cerebral infarction) 
4. Nephrotic syndrome 


 
 
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Event Grade  
(NCI CTC V4.03) and Category 
Action by Agent 
Grade 
Adverse Event 
Carfilzomib 
Cabozantinib 
5. Malignant hypertension, 
hypertensive crisis, 
persistent uncontrolled 
hypertension despite 
optimal medical 
management 
6. Osteonecrosis of the jaw 
7. Reversible posterior 
leukoencephalopathy 
syndrome. 
 
Hepatitis B reactivation 
Any subject who becomes 
HBV DNA positive or 
develops reactivation of 
HBV should have 
carfilzomib treatment 
interrupted and receive 
appropriate anti-viral 
treatment as per a 
specialist in Hepatitis B. 
 
Progressive Multifocal 
Leukoencephalopathy 
(PML) 
Patients should be 
monitored for any new or 
worsening neurologic, 
cognitive or behavioral 
signs or symptoms that 
may be suggestive of 
PML as part of the 
differential diagnosis of 
CNS disorders. 
If PML is suspected, 
patients should be 
promptly referred to a 
specialist and appropriate 
diagnostic testing should 
be initiated.  Discontinue 
Kyprolis if PML diagnosis 
is confirmed. 
 
 
 
Fatigue, Anorexia, and Weight Loss 
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such 
as anemia, deconditioning, emotional distress (depression and/or anxiety), poor nutrition, sleep 
disturbance, and hypothyroidism should be ruled out and/or these causes treated in accordance 
to standard of care. Individual non-pharmacological and/or pharmacologic interventions directed 
to the contributing and treatable factors should be given. Note: Chronic use of modafinil should 
be avoided because of its potential to reduce cabozantinib exposure (see Investigator’s 
Brochure).   
 


 
 
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Anorexia and weight loss should be managed in accordance to local standard of care including 
nutritional support. If fatigue, anorexia, or weight loss cannot be adequately managed, study 
treatment should be temporarily interrupted or dose reduced per protocol.  
 
Perforations and Fistulas: 
Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of cabozantinib treated 
patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI 
fistulas including tracheal/esophageal were reported in 4% of cabozantinib-treated patients. Two 
(1%) of these were fatal. Cabozantinib should be discontinued in patients who experience a 
perforation or a fistula. 
 
Hemorrhage: 
Serious and sometimes fatal hemorrhage occurred with cabozantinib. The incidence of Grade 
3hemorrhagic events was higher in cabozantinib-treated patients compared with placebo (3% 
vs.1%). Cabozantinib should be avoided in patients with a recent history of hemorrhage or 
hemoptysis. 
 
Thrombotic Events: 
Cabozantinib treatment results in an increased incidence of thrombotic events (venous 
thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in cabozantinib-treated 
and placebo-treated patients, respectively). Cabozantinib should be discontinued in patients 
who develop an acute myocardial infarction or any other clinically significant arterial 
thromboembolic complication.  
 
Subjects who develop a PE or DVT should have cabozantinib treatment held until therapeutic 
anticoagulation with heparins (eg, LMWH) is established. LMWH are the preferred management 
for thrombotic events, warfarin is not recommended. Cabozantinib treatment may be resumed in 
subjects who are stable and have uncomplicated PE or DVT and are deriving clinical benefit from 
cabozantinib treatment and that anticoagulation does not place them at a significant risk that 
outweighs the benefit of resuming treatment per discretion of the investigator/Sponsor. 
 
Wound Complications: 
Wound complications have been reported with cabozantinib. Treatment with cabozantinib should 
be stopped at least 28 days prior to scheduled surgery. Therapy can be resumed after surgery 
based on clinical judgment of adequate wound healing. In patients with dehiscence or wound 
healing complications requiring medical intervention, therapy should be withheld. 
 
Hypertension: 
Cabozantinib treatment results in an increased incidence of treatment-emergent hypertension 
with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 
Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in cabozantinib-
treated patients compared with 30% of placebo-treated patients in the randomized trial. Blood 
pressure should be monitored prior to initiation and regularly during cabozantinib treatment. It 
should be withheld for hypertension that is not adequately controlled with medical management; 
when controlled, cabozantinib can be resumed at a reduced dose. It should be discontinued 
for severe hypertension that cannot be controlled with anti-hypertensive therapy. 
 
 
Osteonecrosis of the Jaw: 
Osteonecrosis of the jaw (ONJ) occurred in 1% of cabozantinib-treated patients. ONJ can 
manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, 


 
 
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toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw 
after dental surgery. An oral examination should be performed prior to initiation of cabozantinib 
and periodically during cabozantinib therapy, and patients advised regarding good oral hygiene 
practices. For invasive dental procedures, cabozantinib should be withheld for at least 28 days 
prior to scheduled surgery, if possible.  
 
Palmar-Plantar Erythrodysesthesia Syndrome: 
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with 
cabozantinib and was severe (Grade 3) in 13% of patients. Cabozantinib should be witheld in 
patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 
1 when it can be resumed at a reduced dose. 
 
Proteinuria: 
Proteinuria was observed in 4 (2%) of patients receiving cabozantinib, including one with 
nephrotic syndrome, as compared to none of the patients receiving placebo. Urine protein should 
be monitored regularly during cabozantinib treatment and treatment discontinued in patients 
who develop nephrotic syndrome. 
 
Reversible Posterior Leukoencephalopathy Syndrome: 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical 
vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. An 
evaluation for RPLS should be performed in any patient presenting with seizures, headache, 
visual disturbances, confusion or altered mental function. Discontinuation of cabozantinib 
should occur in patients who develop RPLS.   
 
 
Corrected QTc Prolongation 
Cardiac arrest within 1 day of carfilzomib administration has been reported. If there is QT 
prolongation, we will consider holding carfilzomib.  
 
If at any time on study there is an increase in QTcF to an absolute value > 500 ms or an 
increase of > 60 ms above baseline, two additional ECGs must be performed with intervals not 
less than 3 min apart within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms or increased by > 60 ms above baseline, 
the following actions must be taken: 
• 
Interrupt study treatment 
• 
Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management 
• 
Consider cardiology consultation for asymptomatic subjects for evaluation and management 
• 
Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities as 
clinically indicated 
• 
Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org) 
• 
Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec and the average 
increase is ≤ 60 ms above baseline, or otherwise determined by consultation with a 
cardiologist or appropriate expert. 


 
 
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Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Study treatment may be restarted at a reduced dose 
level if all of the following conditions are met: 
• 
Symptoms are determined to be unrelated to the QT interval prolongation 
• 
Study treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF to ≤ 500 msec or return to ≤ 60 ms above baseline. 
• 
QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved  
• 
Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment 
 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then 
every 2 weeks for 1 month, then according to the protocol-defined time points. 
All study treatment must be permanently discontinued if either of the following applies: 
• 
Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• 
Recurrence of QTcF prolongation (confirmed by central ECG lab) after reinitiation of study 
treatment at a reduced dose 
 
Hypophosphatemia 
Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus 
should be monitored frequently while receiving cabozantinib. Other causes of 
hypophosphatemia should be ruled out and/or these causes treated in accordance to standard 
of care. Mild to moderate hypophosphatemia should be managed by oral replacement including 
food that are high in phosphate (diary items, meats, beans) and/or oral phosphate supplements 
in accordance to standard clinical practice guidelines.  
Clinically relevant hypophosphatemia should be managed in accordance to the dose 
modification guidelines as outlined in the protocol. 
 
Thyroid Function Disorders 
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with 
cabozantinib therapy and other tyrosine kinase inhibitors as a result of altered thyroid hormone 
regulation by mechanisms that seem to be specific for each agent86. Currently available data 
are insufficient to determine the mechanism of TFT alterations and its clinical relevance. 
Routine monitoring of thyroid function and assessments for signs and symptoms associated 
with thyroid dysfunction is recommended before initiation and during treatment with 
cabozantinib. Management of thyroid dysfunction (eg, symptomatic hypothyroidism) should 
follow accepted clinical practice guidelines and dose modification guidelines as outlined in the 
protocol. 
 
Angioedema 
Angioedema should be managed according to standard practice. The subject should be 
observed until symptoms resolve, with particular attention to maintaining an open airway.  


 
 
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Musculoskeletal and Connective Tissue Disorders 
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on 
nonclinical GLP-compliant toxicology studies. The development of new or progressive, 
unexplained musculoskeletal symptoms such as pain or weakness should be assessed for 
underlying causes. 
Rhabdomyolysis has been reported. Cabozantinib should be discontinued in subjects with 
serious and life-threatening rhabdomyolysis and interrupted if less severe forms occur when 
there are no other clear causes. Reinitiation of cabozantinib treatment must be discussed with 
and approved by the sponsor. Therapy of rhabdomyolysis should include supportive care and 
standard medical intervention. 
Respiratory, Thoracic and Mediastinal Disorders 
Dyspnea has been reported in clinical studies with cabozantinib. Symptoms should be managed 
according to locally accepted clinical practice including an assessment for underlying causes. 
Pulmonary embolism should be considered as possible causes for new onset dyspnea given the 
risk of thrombosis associated with inhibition of VEGF signaling. Furthermore, fistula formation 
and pneumonia have been reported in subjects treated with cabozantinib and should be 
considered as clinically indicated in subjects presenting with pulmonary symptoms. 
 
Other 
Treatment of emergent toxicities is at the investigator’s discretion. 
 
5.8 
LABORATORY CORRELATIVE STUDIES 
 
Our central correlative hypotheses propose that:  
 
1. The serum and marrow MUC20 levels which will be judged by flow cytometry and genomic 
studies will directly correlate with primary plasma cell MUC20/c-Met pathway activation and 
inversely correlate with PI resistance; and  
 
2. A correlation of the gene expression and flow cytometry 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. 
 
We plan to quantitate endogenous levels of MUC20 in marrow aspirates and in patient serum 
samples at enrollment and after cycle 2 (prior to start of cycle 3) of therapy using a sensitive flow 
cytometry and GEP assays.   
 
 
 
5.8.1 SAMPLES FOR LABORATORY ENDPOINTS 
 
Bone marrow aspirates will be performed on all patients at baseline and after cycle 2 of therapy, 
and these will be purified into CD138+ and CD138- fractions through the Department of Lymphoma 
& Myeloma’s Myeloma Tissue Bank using standard immunomagnetic bead approaches63.    
Supernatants from marrow aspirate preparations will also be collected, as will concurrent serum 
samples from each patient’s peripheral blood, these samples will be stored at each site, until 
Phase II of the study when efficacy will be assessed. 


 
 
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5.8.2 GENE EXPRESSION PROFILING 
 
Plasma cells purified from the baseline bone marrow aspirate will be subjected to gene expression 
profiling using the “bead array” technology from Illumina.  In this approach, cDNA is first generated 
by priming of mRNA with an oligo-dT primer containing a binding site for T7 RNA polymerase64 
using a kit from Ambion.  This enables the subsequent amplification and generation of biotin-
labeled cRNA.  The starting material is total RNA, and since as little as 25 ng is required, based 
on the published average yield of total RNA65, as well as our own experience63, this can be 
obtained from as few as 5,000 CD138+ myelomatous plasma cells.  Specific transcripts within the 
cRNA are then measured by fluorescent imaging after direct hybridization to HT-12 bead arrays, 
which contain 12 arrays per slide, each with an average of 15 beads for each of >48,000 probes 
measuring >25,000 annotated genes and additional transcripts.  These studies will be performed 
by Dr. Orlowski in collaboration with Dr. R. Eric Davis, the Co-Director of the SPORE Myeloma 
Tissue Core Facility, and an expert in gene expression profiling of primary samples66,67.  Data 
from these studies will be analyzed as described in the subsequent section 10.  Subject to the 
availability of sufficient residual nucleic acid, the expression levels of genes of special interest, 
such as MUC20 and c-Met, will be confirmed by Dr. Orlowski using quantitative real-time 
polymerase chain reaction68,69. 
 
5.8.3 CORRELATION OF MUC20 LEVELS AND RESPONSE TO THERAPY 
 
We plan to quantitate endogenous levels of MUC20 in marrow aspirate supernatants and in 
patient serum samples using a sensitive flow cytometry and ELISA assay.  Given the published 
literature in this area, we anticipate finding that MUC20 levels will be directly inversely correlated 
with PI resistance. MUC20 will inversely correlate with the activation status of the c-Met pathway, 
with the latter to be determined by gene expression profiling. 
 
5.8.4 POTENTIAL PITFALLS 
 
Patients with relapsed, or relapsed and refractory multiple myeloma have varying levels of marrow 
plasmacytosis, and it is therefore possible that, on at least some patients, a low yield of plasma 
cells will be obtained that may limit the ability to do both genomic and proteomic analyses.  
However, our current methods allow for gene expression profiling from as few as 5,000 CD138+ 
myeloma cells63,65. Our experience with these techniques, therefore, gives us confidence that we 
will be able to obtain a fully informative dataset from the vast majority of patients treated on this 
study. 
 
The intent is to utilize all of the marrow aspirate and serum samples collected for the correlative 
studies, however, should we not see a clinical response (efficacy) in Phase II of the study, the 
above correlative analysis may not be performed and the samples will be maintained at each site 
for future unspecified used. 
 
 
 
5.9 
SYMPTOM INVENTORY AND QUALITY OF LIFE 
 
5.9.1 M. D. ANDERSON SYMPTOM INVENTORY (MDASI) 
 


 
 
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Symptoms will be measured by the multiple myeloma module of the MDASI (MDASI-MM, 
Appendix B).  The MDASI is a multiple-symptom assessment tool for measuring of cancer-related 
symptoms70 that is sensitive to disease and treatment changes71.  This instrument is brief, easily 
understood, and validated in the cancer population.  Patients rate the severity of 13 physical, 
affective, and cognitive symptoms on 0–10 numeric scales, ranging from “not present” to “as bad 
as you can imagine.”  The recall period is for the last 24 hours.  The MDASI-MM has 7 additional 
items known to be important in assessing multiple myeloma patients (constipation, muscle 
weakness, diarrhea, sore mouth or throat, rash, concentration and bone aches).  The MDASI-MM 
takes less than 5 minutes to complete either by self-report or study staff personal interview, using 
paper format, tablet PC, or via an automated system, such as a telephone-based interactive voice 
response (IVR).   Symptom severity and interference will be the variables of interest to correlate 
to clinical outcomes and biomarkers. 
 
This tool is to be administered at baseline, at the start of each cycle, half-way through 
each cycle, and at the end-of-study visit. 
 
5.9.2 QUALITY OF LIFE / PATIENT REPORTED OUTCOMES 
 
The European Organization for Research and Treatment of Cancer (EORTC) sought, starting in 
1986, to develop an integrated, modular approach to evaluate the quality of life of patients with 
malignant disorders who were participating in clinical trials.  This effort resulted in the Quality of 
Life Questionnaire (QLQ) Core 30 (QLQ-C30) tool, which was initially tested in an international 
field study to determine its practicality, reliability, and validity72.  Nine multi-item scales were 
incorporated into QLQ-C30, including five functional scales (physical, role, cognitive, emotional, 
and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health 
and quality-of-life scale.  In the first validation study, the questionnaire was administered to 305 
patients with unresectable lung cancer in 13 countries.  Notably, the average time needed to 
complete the questionnaire was about 11 minutes, and most patients could do this without 
assistance.  Validity was supported by the fact that all interscale correlations were statistically 
significant, the correlation was moderate, indicating that the scales were assessing different 
quality-of-life construct components; that most of the functional and symptom measures 
discriminated clearly between patients differing in clinical status as defined by the ECOG 
performance status scale, weight loss, and treatment toxicity; and that there were statistically 
significant changes in physical and role functioning, global quality of life, fatigue, and nausea and 
vomiting, for patients whose performance status had improved or worsened72.   
 
Since this initial version of QLQ-C30, a number of other, later versions have been developed, 
which incorporated changes such as the addition of single items assessing other symptoms and 
perceived financial impact of the disease.  Later, four-point scales were used for the first five 
items, and some questions were rephrased, leading to the current version, 3.0, which is the 
standard that is used for all new studies73.  Notably, the QLQ-C30 has been successfully used in 
a number of multiple myeloma studies, including trials targeting younger and older patients, newly 
diagnosed and relapsed or relapsed/refractory patients, and patients undergoing standard or high 
dose therapies70,71. 
 
A multiple myeloma-specific module has also been designed, and is intended to be used in clinical 
trials with the EORTC QLQ-C30.  This questionnaire uses a one-week time frame, and response 
categories are consistent with the EORTC QLQ-C30.  After testing studies in patients with multiple 
myeloma, a review of the results obtained in each stage of development resulted in an initial 24-
item myeloma-specific module, the EORTC QLQ-MY2474, which assesses disease-specific 
symptoms and their impact on everyday life, treatment side-effects, social support, and future 


 
 
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perspective.  Like the QLQ-C30, the QLQ-MY24 has been successfully used in a number of 
different clinical trial settings.  
 
These tools will be administered at baseline, at the start of each cycle, and at the end-of-
study visit. 
 
 
6. 
MEASUREMENT OF EFFECT 
 
Restaging 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).  Responses 
will be determined using the European Group for Blood & Marrow Transplantation (EBMT)75  and 
International Myeloma Working Group (IMWG) Uniform Response Criteria76. 
 
 
6.1 
RESPONSE QUALITY 
 
Responses to cabozantinib will be determined predominantly using the recently published76 
consensus recommendations for the uniform reporting of clinical trials from the International 
Myeloma Working Group.  These guidelines provide for the following response categories:  
 Complete Response (CR) 
o Negative immunofixation of the serum and urine, and 
o Disappearance of any baseline soft tissue plasmacytomas, and 
o < 5% plasma cells in the bone marrow 
 Stringent Complete Response (sCR) 
o CR as defined above, plus 
o Normal serum free light chain (FLC) ratio, and 
o Absence of clonal plasma cells (PC) by immunohistochemistry, or by 
immunophenotyping with 2 - 4 color flow cytometry 
 Very Good Partial Response (VGPR) 
o Serum and urine M-component still detectable by immunofixation but not on 
electrophoresis, or 
o ≥ 90% or greater reduction in serum M-component plus a urine M component of < 
100 mg per 24 hours 
 Partial Response (PR) 
o ≥ 50% reduction of the serum M-protein and a reduction in the 24 hour urinary M-
protein by ≥ 90%, or to < 200 mg per 24 hours 
o If the serum and urine M-protein are not measurable, a ≥ 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria 
o If serum and urine M-proteins are not measurable, and serum free light assay is 
also not informative, ≥ 50% reduction in bone marrow plasma cells is required in 
place of the M-protein, provided the baseline percentage was ≥ 30% 
o In addition to the above criteria, if present at baseline, a ≥ 50% reduction in the 
size of any soft tissue plasmacytomas is also required 
 Stable Disease (SD) 
o Any measurements not meeting criteria for CR, VGPR, PR or progressive disease 


 
 
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 Progressive Disease (PD) 
o 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 
 
Only in patients without a measurable serum and urine M protein level, and 
without measurable disease by FLC levels, bone marrow plasma cell 
percentage (absolute %) must be >10% 
 
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 
 
Notably, all of the response categories (CR, sCR, VGPR, PR, and PD) require two consecutive 
assessments made at anytime before the institution of any new therapy.  Also, the CR, PR, and 
SD categories require no known evidence of progressive or new bone lesions if radiographic 
studies were performed, and the VGPR and CR categories require serum and urine studies 
regardless of whether disease at baseline was measurable on serum, urine, both or neither.  
Radiographic studies are not required to satisfy these response requirements, and bone marrow 
assessments need not be confirmed. 
 
In addition to the above definitions, a modification of the uniform criteria will be made for the 
purposes of this study by introducing the following criterion: 
 Minor Response (MR) 
o Between 25 - 49% reduction in serum M protein, maintained for a minimum of 
6 weeks 
o Between 50 - 89% reduction in urinary light chain excretion which still exceeds 
200 mg/24 hours, maintained for a minimum of 6 weeks 
o For subjects with non-secretory myeloma only, between 25 - 49% reduction in 
plasma cells in a bone marrow aspirate or a bone trephine biopsy, if biopsy is 
performed, maintained for a minimum of 6 weeks 
o Between 25 - 49% reduction in the size of extramedullary plasmacytomas 
o If a skeletal survey is performed, no increase in the size or number of lytic lesions 
(development of a compression fracture does not exclude response). 
 
 
6.2 
RESPONSE QUANTITY 
 
Using the above measures of response quality, the current study will seek to define, on an intent 
to treat basis, the following parameters: 
 
 Overall Response Rate (ORR) 
o CR + sCR + VGPR + PR 
 Clinical Benefit Response Rate (CBR) 
o CR + sCR + VGPR + PR + MR 


 
 
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6.3 
RESPONSE DURABILITY 
 
In addition to response quality and quantity, the current study will measure response  
durability based on the following: 
 Time to Progression (TTP) 
o Duration from the start of treatment to disease progression, with deaths due to 
causes other than progression censored 
 Progression-free Survival (PFS) 
o Duration from start of the treatment to disease progression or death (regardless of 
cause of death), whichever comes first 
 Duration of Response (DOR) 
o Duration from first observation of partial response to the time of disease 
progression, with deaths due to causes other than progression censored 
 Time to Next Treatment (TTNT) 
o Time from registration on trial to next treatment or death due to any cause, 
whichever comes first 


 
 
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7. 
STUDY CALENDAR AND ASSESSMENTS 
 
Table 7.1.  Study Time and Events Table 
 
Study Phase 
Screening 
     Treatment 
 
End 
Study Cycle 
/ 
c1 
2 
≥3 
/ 
Study Day 
-28 to -1 
1 
8 
15 
22 
1 
15 
1 
15 
 
Assessment 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
Within 
30 days 
of D/C 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Comprehensive history 
X 
 
 
 
 
 
 
 
 
X 
Comprehensive physical examination 
X 
 
 
 
 
 
 
 
 
X 
Interval (abbreviated) medical history 
 
X 
 
X 
 
X 
 
X 
 
 
Symptom-directed (abbreviated)  physical 
examination 
 
X 
 
X 
 
X 
 
X 
 
 
Oral Examination13 
X 
[----------------as clinically indicated-------------------] 
Verification of study eligibility 
X 
X 
 
 
 
 
 
 
 
 
Vital signs, including weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
 
X 
 
X 
 
X 
 
X 
Echocardiogram (TTE) 
X 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
X10 
X1 
 
 
 
X1 
 
X1, 11 
 
X 
Posteroanterior & lateral chest radiograph 
X 
 
 
 
 
 
 
 
 
 
Skeletal survey for lytic lesions 
X 
 
 
 
 
 
 
 
 
 
Computed tomography of plasmacytomas, if 
indicated by SOC 
X2 
 
 
 
 
 
 
X2 
 
 
Complete blood count, differential, platelet count 
X 
X3,4 
X3 
X3 
X3 
X 
 
X 
 
X 
CD4+ cell count in patients who are HIV-positive 
X 
 
 
 
 
 
 
 
 
 
Hep B screen12  
X 
 
 
 
 
 
 
 
 
 
Hep B-DNA monitoring12 
 
[-----------as clinically indicated---------------] 
 
Sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose 
X 
X4 
 
X 
 
X 
 
X 
 
X 
Calcium, phosphorous, magnesium 
X 
X4 
 
X 
 
X 
 
X 
 
X 
Alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, alkaline 
phosphatase, lactate dehydrogenase, uric acid 
 
X 
 
X4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Total protein, albumin 
X 
X4 
 
X 
 
X 
 
X 
 
X 
β-2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
Thyroid stimulating hormone (TSH) 
X8 
 
 
 
 
 
 
 
 
 
β-human chorionic gonadotropin level 
X5 
X5 
 
 
 
X5 
 
X5 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
Prothrombin & activated partial thromboplastin times 
X 
X4 
 
 
 
X9 
 
X9 
 
 
Serum protein electrophoresis and immunofixation, 
quantitative immunoglobulins 
X 
X6 
 
 
 
X 
 
X 
 
X 
Serum free κ and λ light chains and κ/λ ratio 
X 
X6 
 
 
 
X 
 
X 
 
X 
24-hour urine protein electrophoresis & 
immunofixation 
X 
X6 
 
 
 
X 
 
X 
 
X 
Disease status to determine eligibility to continue with 
further therapy with cabozantinib 
 
 
 
 
 
 
 
X 
 
 
Bone marrow aspiration and biopsy (study samples 
taken also) 
X 
 
 
 
 
 
 
X7 
 
 
Serum sample for MUC20  
X4 
 
 
 
 
 
 
X4 
 
 
M. D. Anderson Symptom Inventory – Multiple 
Myeloma tool (MDASI–MM) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Quality of Life Questionnaires (QLQ-C30, QLQ–M20) 
 
X 
 
 
 
X 
 
X 
 
X 
Dispense/collect patient study medication diary 
X 
 
 
 
 
X 
 
X 
 
X 


 
 
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1 To evaluate if there is an increase in QTcF to an absolute value > 500 ms or an increase of > 60 ms above 
baseline.  See section 5.7.1 for more details.  
2If indicated for initial measurement, and then for confirmation of complete response as directed by SOC. 
3Complete blood cell counting will be performed weekly in cycle 1 only. 
4These studies can be performed within 3 days of the indicated day.  In cycles ≥ 3 serum sample will be drawn 
prior to cycle 3 only. 
5Only in women of child-bearing potential. 
6These tests should not be repeated if they were performed within fourteen days during the screening period. 
7To evaluate response, a bone marrow aspiration and biopsy will be performed once, as well as bone marrow 
aspirate extra tube  for MUC20 correlative studies.  In cycles ≥ 3 study sample will be taken prior to cycle 3 only. 
8TSH will be tested every three cycles if subject continues past cycle 3. 
9 Subjects receiving LMWH for therapeutic anticoagulation or thromboprophylaxis, will have PT/PTT coagulation 
parameters at the start of each cycle while on study treatment.  
10 Baseline ECG see Exclusion criteria #18 for details. Of note, the ECG should be performed 1 to 14 days prior 
to starting treatment. 
11 Beyond C3 ECG is performed every 12 weeks.  
12  If baseline hepatitis B serology status is unknown, please perform.  For monitoring, carriers of HBV who being 
treatment with carfilzomib should be closely monitored for signs and symptoms of active HBV infection 
throughout treatment. Any subject who becomes HBV DNA positive or develops reactivation of HBV should have 
carfilzomib treatment interrupted and receive appropriate anti-viral treatment as per a specialist in Hepatitis B. 
13 Note: the oral examination can be completed as part of an ENT referral visit 
 
 
8. 
Drug Formulation and Procurement 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study found below in Section 8.1.7. 
 
8.1 
Cabozantinib   
 
Please consult the most current Investigator’s Brochure and package insert for complete drug 
information. At study sites, all study medication will be stored and inventoried in accordance 
with applicable state and federal regulations. 
8.1.1 Chemical Name 
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane- 
1,1-dicarboxamide, (2S)-hydroxybutanedioate 
 
8.1.2  Cabozantinib Tablets 
 
For this clinical trial cabozantinib is supplied as film coated tablets containing cabozantinib 
malate equivalent to 20 mg of cabozantinib and contain microcrystalline cellulose, lactose 
anhydrous, hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium 
stearate and Opadry® yellow. All tablet strengths are prepared from a common blend and are 
distinguished by shape. The 20 mg tablets are round.  
 


 
 
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Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910/Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 
8.1.3  Preparation and storage:   
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 
86°F).  Stability information submitted includes forced degradation, heat stress, light stress and 
long-term studies. These studies indicate sensitivity to acid hydrolysis (formation of ordinary 
impurities) and high heat (formation of genotoxic impurities).  
 
8.1.4  Administration:  
Oral.  Patients will receive cabozantinib at a starting dose of 20 mg P.O. once daily continuously 
during days 1-28 of a 28-day cycle. Should unacceptable toxicities occur at 20 mg, there will be 
no de-escalation dose and the study will be halted. If there are no toxicities observed on initial 
dose of 20 mg PO daily, the dose will be escalated to 0 level of 40 mg PO daily in the same 
manner. If no toxicities observed, further dose escalation to +1 level of 60 g PO daily will be  done. 
Cabozantinib will be given 1-2 days prior to carfilzomib in three additional patients enrolled.  
 
Cabozantinib must be taken on an empty stomach.  Patients taking cabozantinib tablets should 
be instructed not to eat for at least 2 hours before and at least 1 hour after taking cabozantinib.  
Subjects should be instructed to take their cabozantinib dose at approximately the same time 
every day.  If a subject misses a dose, the dose may be taken later only if it is within 12 hours of 
when the missed dose should have been taken.  The missed dose should not be made up if it is 
within 12 hours of the next scheduled dose.   
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water.  The tablets 
should be swallowed whole with water, and cannot be crushed or broken.  Grapefruit, grapefruit 
juice, Seville oranges and their products should be avoided by subjects taking cabozantinib. 
 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 5.7. 
 
8.1.5  Potential Drug Interaction:    
Cabozantinib is metabolized via a drug metabolizing enzyme system associated with cytochrome 
P450 (CYP3A4).  Interactions with drugs metabolized via the same enzyme system are possible.  
Drugs which inhibit CYP3A4 may markedly increase the plasma concentration of cabozantinib.  


 
 
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Drugs and substances which inhibit CYP3A4 may increase the plasma concentrations of 
cabozantinib.   
 
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 
 
http://medicine.iupui.edu/flockhart/table.htm 
 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm080499.htm   
 
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, 
highly protein bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of cabozantinib and/or 
a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic 
effect). 
8.1.6 Other Interactions:  
Food may increase exposure levels of cabozantinib by 57%, fasting recommendations should 
be followed. Subjects should fast (with the exception of water) for at least 2 hours after eating 
the evening meal before taking their dose of cabozantinib. After the 2-hour fast and before going 
to bed, subjects are to take cabozantinib with a full glass of water (minimum of 8 oz or 240 mL) 
with no more food intake for one hour post-dose. 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein, but it does 
appear to have the potential to inhibit the P-glycoprotein transport activity. Therefore, 
cabozantinib may have the potential to increase plasma concentrations of co-administered 
substrates of P-glycoprotein.  
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure. 
 
8.1.7  Known potential toxicities: 
Cabozantinib treatment-emergent adverse events/serious adverse events of particular interest 
• 
Gastrointestinal disorders (diarrhea, nausea and vomiting , dehydration [prostate cancer 
studies], stomatitis and mucositis) 
• 
Hepatobiliary disorders (elevated ALT and AST)  
• 
Hematological disorders 
• 
Fatigue, anorexia, and weight loss 
• 
Skin disorders (palmar-plantar erythrodysesthesia syndrome [PPES] and rash) 


 
 
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• 
Wound healing and surgery 
• 
Hypertension 
• 
Thromboembolic events (venous and arterial) 
• 
Proteinuria 
• 
QTc prolongation 
• 
Hypophosphatemia 
• 
Thyroid function disorders  
• 
Hemorrhagic events 
• 
Osteonecrosis of the jaw (ONJ) 
• 
Angioedema 
• 
Musculoskeletal and connective tissue disorders 
• 
Respiratory, thoracic, and mediastinal disorders 
 
8.1.8  Drug procurement:  
Cabozantinib is an investigational agent supplied to investigators by Exelixis, Inc. 
 
8.2  
Carfilzomib  
 
 
8.2.1  Preparation and storage: 
Carfilzomib is currently FDA approved for the treatment of patients with multiple myeloma who 
have received at least two prior therapies including bortezomib and an immunomodulatory agent 
and have demonstrated disease progression on or within 60 days of completion of the last 
therapy. KYPROLIS (carfilzomib) is administered intravenously over 10 minutes, on two 
consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day 
rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. 
 
8.2.2  Known potential toxicities: 
Carfilzomib each may cause low blood cell counts (red blood cells, platelets, 
and/or white blood cells): 
• A low red blood cell count (anemia) may cause difficulty breathing 
and/or fatigue. You may need a blood transfusion. 
• A low platelet count increases your risk of bleeding (such as 
nosebleeds, bruising, stroke, and/or digestive system bleeding). You 
may need a platelet transfusion. 
• A low white blood cell count increases your risk of infection (such as 
pneumonia and/or severe blood infection). Infections may occur 
anywhere and become life-threatening. Symptoms of infection may 
include fever, pain, redness, and difficulty  breathing. 
 
Very Common (may affect more than 1 in 10 patients) 
 


 
 
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• swelling of hands, feet or 
ankles 
• headache 
• high blood pressure 
• pain 
• muscle spasms 
• fever 
• fatigue 
• nausea 
• stomach pain 
• vomiting 
• diarrhea 
• constipation 
• respiratory tract infections 
• lung infection 
• 
• low blood cell counts 
(red, platelets, white) 
• runny nose or nasal 
congestion 
• decreased blood levels of 
potassium 
• high blood sugar and/or 
creatinine 
 
• dizziness 
• weakness 
• numbness 
• difficulty sleeping  
• infusion reaction 
• back pain 
• joint pain 
• pain in limbs (hands or 
feet) 
 
     Common (may affect up to 1 in 10 patients) 
 
• heart failure and heart 
problems including rapid 
strong or irregular heart 
beat  
• possible fluid in the lung  
• chills 
• pulmonary hypertension 
• rash 
• itchy or redness of skin 
• increased sweating 
 
• blood clot in the lungs 
• nose bleed 
• change in voice; 
hoarseness 
• wheezing 
decreased blood levels of 
sodium, magnesium, 
protein, calcium or 
phosphate 
• high blood levels of 
calcium, uric acid, 
potassium, bilirubin, or c-
reactive protein 
• low blood pressure 
• blood clots in veins 
• bone and muscle pain 
muscle weakness 
• kidney problems, 
decreasing ability to make 
urine and failure 
• anxiety 
 
Uncommon (may affect up to 1 in 100 patients) 
 


 
 
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• decreased or worsening 
of heart function  
• severe increase in blood 
pressure  
• stroke 
• build-up of fluid around the 
heart 
• inflammation of the tissue 
around the heart 
• decreased blood supply 
to the heart 
• bleeding around the 
brain 
• bleeding in the 
stomach and bowels 
• hole in the intestines 
(possible leaking 
contents into the 
abdomen) 
• itchy skin, yellowing 
of the skin and/or 
eyes caused by 
blocking of bile flow 
from the liver  
• liver failure 
• bleeding in the lungs 
• increased blood 
pressure in the lungs 
(possible difficulty 
breathing and/or heart 
failure) 
• lung inflammation 
(possible difficulty 
breathing) 
• multi organ failure 
 
• blockage in the lung 
(possible pain and/or 
shortness of breath) 
allergic reaction to 
carfilzomib 
• breakdown products of 
the cancer cells entering 
the blood stream (Tumor 
Lysis Syndrome)  
 
 
Rarely, Thrombotic thrombocytopenic purpura/Hemolytic uremic syndrome (TTP/HUS); 
Thrombotic microangiopathy; Posterior reversible encephalopathy syndrome (PRES) have been 
reported in patients taking carfilzomib. 
 
The following side effects have been seen in people who received carfilzomib. It is unknown if 
they were caused by carfilzomib: 
• 
Tiredness, infection, and easy bruising or bleeding which may be symptoms of a blood 
condition known as Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML). 
• 
Tenderness of pain in the abdomen that gets more intense with motion or touch, 
abdominal bloating or distention, nausea and vomiting, diarrhea, constipation or the 
inability to pass gas which may be symptoms of swelling of the thin tissue that lines the 
inner wall of the abdomen and covers most of the abdominal organs 
Driving and Using Machines 
You may experience fatigue, dizziness, fainting, and/or a drop in blood pressure after treatment 
with carfilzomib. This may impair your ability to drive or operate machinery. If you have these 
symptoms, you should not drive a car or operate machinery. 
 
Hydration Risks 
There may be risks associated with over hydrating (having too much fluid in your body) so it is 
important to follow your doctor’s instructions regarding how much water or other fluids you 
should drink. Over hydration can cause side effect to your heart, lungs, and kidneys. 
 
8.2.3  Drug procurement: Commercially available. 
 
8.2.4 Nursing guidelines 


 
 
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In order to control the dosing of carfilzomib while combined with cabozantinib in this trial, patients 
will receive carfilzomib at a maximum capped starting dose of 27 mg/m2 intravenously over 10 
minutes provided that they tolerated that dose with only grade 1 toxicities as specified above in 
the inclusion criteria.. Carfilzomib will be administered on two consecutive days each week for 3 
weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28).  
 
Patients will also be allowed to continue with Dexamethasone at a capped dose of 40 mg (for 
patient age ≥ 75, acceptable to be given as 20 mg PO/IV) weekly. 
 
 


 
 
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9.  Toxicity and Adverse Event Reporting Guidelines 
 
Adverse event monitoring and reporting is a routine part of every clinical trial.   
 
This protocol will comply with monitoring and adverse event reporting requirements of the 
UNMC Fred & Pamela Buffett Cancer Center Data Monitoring plan. The protocol will adhere to 
the institutional and FDA guidelines for the toxicity reporting. 
 
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 ≤ grade 1 levels. Toxicity will be assessed using the revised NCI 
CTCAE version 4.03.  
 
All adverse events will be followed to a satisfactory conclusion. Serious adverse events should 
be followed until resolution, death, or until no further improvement is reasonably expected. 
Deaths occurring within 30 days of study treatment regardless of relationship will be reported to 
UNMC DSMC. 
 
In addition to complying with all applicable regulatory reporting laws and regulations, all serious 
adverse events and toxicities will be reported to the University of Nebraska Medical Center, 
Institutional Review Board (IRB), participating sites own IRB and Fred & Pamela Buffett Cancer 
Center Data and Safety Monitoring Committee (DSMC). 
 
Definitions:  
Adverse Event  
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not the event is considered causally related to the use of the product.  
 
An elective surgery or procedure that is scheduled to occur during a study will not be considered 
an adverse event if the surgery or procedure is being performed for a pre-existing condition and 
the surgery or procedure has been planned before study entry. However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., the surgery is performed earlier than 
planned), then the deterioration of the condition for which the elective surgery or procedure is 
being done will be considered an adverse event.  
 
An adverse event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening 
of a pre-existing condition or illness is considered an adverse event. Laboratory abnormalities 
and changes in vital signs are considered to be adverse events if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meet protocol specific criteria (see 
Section 5.0, Treatment Plan) and/or if the investigator considers them to be adverse events. In 
general, if a laboratory abnormality or change in vital sign is associated with a specific diagnosis 
that is being reported concurrently as an adverse event (e.g. elevated creatinine with renal 
failure or sinus tachycardia in febrile neutropenia) the findings that support the diagnosis do not 
need to be reported as separate adverse events unless the investigator feels it is appropriate.  
 
 


 
 
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Treatment-emergent Adverse Event  
Treatment-emergent adverse event is defined as any adverse event with onset or worsening 
from the time that the first dose of study drug is administered until 30 days after the final dose of 
study drug is administered.  
 
Unexpected Adverse Event  
An unexpected adverse event is any adverse drug event that is not listed in the current 
labeling/Investigator’s Brochure. This includes events that may be symptomatically and 
pathophysiologically related to an event listed in the labeling, but differ from the labeled event 
because of greater severity or specificity. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the labeling only referred to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would 
be unexpected (by virtue of greater specificity) if the labeling only listed cerebral vascular 
accidents. “Unexpected,” as used in this definition, refers to an adverse drug experience that 
has not been previously observed (i.e., included in the labeling) rather than from the perspective 
of such experience not being anticipated from the pharmacological properties of the 
pharmaceutical product.  
 
Serious Adverse Event  
A serious adverse event is one that at any dose (including overdose) and regardless of causality 
that:  
• 
Results in death  
• 
Is life-threatening1  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity2  
• 
Is a congenital anomaly or birth defect  
• 
Is an important medical event3  
 
1 “Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe.  
2 “Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions.  
3 Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred. 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be 
considered serious. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. A new diagnosis of cancer during the course of a treatment should be 
considered as medically important. 
 
9.1 
Adverse Event Reporting and Definitions Per University of Nebraska 
Medical Center, IRB and Fred & Pamela Buffett Cancer Center Data and Safety 
Monitoring Committee (DSMC) and Exelixis  
 
This protocol will adhere to all institutional guidelines for adverse event reporting. Adverse 
events will be evaluated using the NCI Common Terminology Criteria for Adverse Events (CTC-


 
 
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AE) version 4.03.  
 
9.1.1 IRB REPORTING  
 
All internal serious adverse events (AEs) must be reported to the local IRB promptly per 
institutional human research protection program policies.   
 
9.1.2 FRED & PAMELA BUFFETT CANCER CENTER DATA AND SAFETY MONITORING 
COMMITTEE (DSMC) REPORTING 
 
All adverse events whether internal or external, will be reported to the UNMC Fred & Pamela 
Buffett Cancer Center Data and Safety Monitoring Committee (DSMC) as noted in Section 
9.3.2. In its initial review, the DSMC will make a recommendation for the frequency of DSMC 
monitoring based on an assessment of risk associated with study-associated therapy, per 
DSMC policy.  
 
All adverse events ≥ grade 3 (expected or unexpected, regardless of attribution) will be reported 
to the University of Nebraska Medical Center, Fred & Pamela Buffett Cancer Center Data and 
Safety Monitoring Committee (DSMC) in accordance with DSMC guidelines.  
 
Attribution of AE: The likelihood of relationship of the AE to the study drugs will be determined 
by the investigator based on the following definitions:  
 
Not related: The subject was not exposed to the study treatment or another cause is obvious.  
 
Probably not related: The AE is most likely explained by another cause, and the time of 
occurrence of the AE is not reasonably related to the study treatment. 
  
Possibly related: Study treatment administration and AE occurrence reasonably related in 
time, and the AE is explained equally well by causes other than study treatment, or 
treatment administration and AE occurrence are not reasonably related in time, but the 
AE is not obviously a result of other causes.  
 
Probably related: Study treatment administration and AE occurrence are reasonably related in 
time, and the AE is more likely explained by study treatment than by other mechanisms.  
 
Definitely related: There occurrence and timing of the AE are clearly attributable to the study 
treatment.  
 
Severity Grade of AE. The severity of events reported on the AE case report form will be 
determined by the principal investigator according the NCI Common Toxicity Criteria 
(CTC version 4.03).  
 
AEs will be collected from the time the subject signs the consent form and ending 30 
days following the final chemotherapy. All AEs will be followed until resolution or a cause 
is identified. Prescription medication taken to relieve symptoms of the AE will be 
recorded in addition to the outcome.  
 
AEs judged by the investigator as not related or probably not related to the treatment will 
NOT be followed beyond the 30 days after the final chemotherapy.  
 


 
 
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Transplant related Adverse Experiences (AE’s) or Serious Adverse Experiences (SAE’s) 
will NOT be collected.  
 
Copies of the AE report will be submitted to the IRB as indicated in Section 9.1.1.  
 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html 
 
9.1.3  FOOD AND DRUG ADMINISTRATION (FDA) REPORTING 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 


 
 
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2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
9.1.4 Exelixis and Amgen Reporting requirements 
 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
should be documented to the extent that information is available. 
• 
Investigator shall notify Exelixis and Amgen within twenty-four (24) hours of making such 
discovery by submitting a completed SAE report form and any other pertinent SAE 
information as indicated on the SAE reporting form; 
• 
For multicenter studies the Investigator must notify the IND/CTA Sponsor by submitting 
a completed SAE report form and any other pertinent SAE information as indicated on 
the SAE reporting form within 24 hours. The site will also submit the SAE report form to 
Exelixis and Amgen no later than 2 business days. 
• 
This report must be submitted by Institution to Exelixis at e-mail: 
drugsafety@exelixis.com or fax 650-837-7392, even if it is not felt to be drug related; 
and to Amgen Global Safety Toll-free 1-888-814-8653. 
• 
Pregnancy (for a subject or for the partner of a subject), although not itself an SAE, 
should also be reported on a pregnancy form and be followed up to determine outcome, 
including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects or congenital abnormalities; 
• 
SAEs that must be recorded on an SAE Reporting form include the following: 
o all SAEs that occur after informed consent and through 30 days after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen 
failure); 
o any SAEs assessed as related to study treatment or study procedures, even if 
the SAE occurs more than 30 days after the decision to discontinue study 
treatment; 
o although most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: elective or previously 
scheduled surgeries or procedures for pre-existing conditions that have not 
worsened after initiation of treatment (eg, a previously scheduled ventral hernia 
repair); pre-specified study hospitalizations for observation; or events that result 
in hospital stays of fewer than 24 hours and that do not require admission (eg, an 
emergency room visit for hematuria that results in a diagnosis of cystitis and 
discharge to home on oral antibiotics). SAEs must, however, be reported for any 
surgical or procedural complication resulting in prolongation of the 
hospitalization. 


 
 
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Pregnancy 
If a subject becomes pregnant during the study, she will be taken off study treatment and will be 
followed through the end of her pregnancy. The investigator must inform the Sponsor of the 
pregnancy. Forms for reporting pregnancies will be provided to the study sites upon request. 
The outcome of a pregnancy (for a subject or for the partner of a subject) and the medical 
condition of any resultant offspring must be reported to Exelixis and Amgen or designee. Any 
birth defect or congenital anomaly must be reported as an SAE, and any other untoward events 
occurring during the pregnancy must be reported as AEs or SAEs, as appropriate. 
Medication Errors/Overdose 
Any study drug administration error or overdose that results in an AE, even if it does not meet 
the definition of serious, requires reporting within 24 hours to Exelixis and Amgen or designee. 
9.2 Auditing  
Auditing is a systematic and independent examination of trial-related activities and documents 
to determine: 
• 
whether the evaluated trial-related activities were conducted 
• 
 the data were recorded, analyzed, and accurately reported, according to the protocol, 
to the sponsor's SOPs, GCP, and applicable regulatory requirement(s).  
 
Auditing is a Quality Assurance, one point process during the trial. 
 
 
This study will undergo audit on at least a semi-annual basis by the UNMC Fred & Pamela 
Buffett Cancer Center Audit Committee.  
 
For participating site(s) that are NCI Cancer Centers, the protocol specific finding of the 
participating site’s Audit Committee will be submitted to the UNMC Audit Committee for review 
on a schedule to be determined by the UNMC Audit Committee. For participating site(s) that are 
not NCI Cancer Centers, the audit process will be established by the UNMC Audit Committee 
on a site-by-site basis. 
 
 
Detailed policy and procedures for this section may be reviewed at: 
http://www.unmc.edu/cancercenter/clinical/prms.html.  
 
9.3 Monitoring  
 
9.3.1  Various methods will be implemented by the sponsor (UNMC) to exchange 
information with participating sites:  
 
• Site Initiation/Orientation  
• Regular Teleconferences including group wide progress within the agenda  
• Investigator meetings as feasible (remote or TBA, possibly in conjunction 
with larger meetings)  
• Email distributions/reports as needed  
• Drug company Safety Updates  
 
9.3.2  Ongoing data monitoring for all the subjects in this study:  
 


 
 
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For this study, data monitoring is the act of overseeing the progress of a clinical trial, and of 
ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirement(s).  Monitoring is a Quality Control, continuous process during the entire trial. 
 
UNMC or a representative for UNMC will monitor the data of participating sites in adherence 
to applicable research regulations, the protocol, and the site agreement. The sponsor may 
request de-identified source documents that support data entered by mail, fax, or electronic 
means for centralized compliance monitoring. 
 
10.  STATISTICAL CONSIDERATIONS 
 
10.1 Study Design and Sample Size Description 
 
This Phase I/II study has two primary aims.  The first primary aim is to determine the MTD that 
will be chosen as RP2D among three doses. DLTs will be based solely on adverse events that 
occur during cycle 1, while the RP2D will be chosen taking into consideration any toxicities that 
may potentially arise beyond cycle 1.  A DLT is defined as treatment-related unmanageable 
toxicities, including grade 3 non-hematologic effects, or grade 4 hematologic effects, that require 
delay or termination of the treatment during cycle 1.  We will study three dose levels using the 
3+3 algorithm. Overall, depending on the dose escalation portion, the minimum number of study 
patients enrolled should both phases (I and II) be successful is 26 (23+3), and the maximum 32 
(29+3); additional 3 patients represent adjustment to meet the goal of total evaluable patients at 
the end of the study, accounting for the treatment discontinuation rate of 7% in the METEOR 
study.   
 
The second primary aim of the study is to determine the ORR.  Response will be determined by 
the IMWG response criteria guidelines. All subjects in phase I that receive the RP2D will be 
included in phase II study analysis.  We will use a Simon two-stage design to compare response 
rates of 0.25 versus 0.05 with alpha=0.05 and power of 0.8083.  A minimum of nine patients will 
be enrolled in the first stage. The first interim analysis would be performed, as the hypothesis 
will be rejected and enrollment will cease if no response is seen in the first 9 patients enrolled 
on the Phase II portion of the study.   Otherwise, another 14 patients will be accrued for a total 
of 17 evaluable patients. If, there has already been at least one documented response in the first 
9 patients, then accrual will be continued into the second stage without interruption.  However, if 
there have not been any documented responses in the first 9 patients, accrual will be halted to 
allow for all patients to complete at least two cycles of therapy, at which time they will be 
considered evaluable for disease response.  At the end of the trial, the drug will be rejected if no 
more than 2 responses are seen in the total of 17 evaluable patients.  
 
This study has several secondary aims:  
(1) To describe and tabulate the toxicities of cabozantinib in this specific patient population, which 
will be graded according to the CTCAE, version 4.03; 
(2) To describe GEP values as well as MUC20 level of expression in patients at baseline and 
after cycle 2 of therapy;  
(3) response durability, the earliest of progression, death, or loss to follow-up, and the time to next 
treatment;  
(4) symptom burden as quantified by the MD Anderson Symptom Inventory and its MM module;  


 
 
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(5) evaluation of the impact of cabozantinib on signaling through the c-MET/ERK-1/2/ELK1 
/POMP using genomic assays by comparing primary plasma cells obtained from bone marrow 
aspirates obtained at baseline, and after cycle 2 of therapy.  
 
10.2  Analytic Plan 
For the phase I study, we will examine three doses, with the first cohort assigned to 20 mg orally 
daily dose.  The MTD will be defined via the 3+3 algorithm, i.e. as the dose level below the one 
at which 1/3 or 2/6 patients experience DLTs. At the completion of the phase II section, the ORR 
will be estimated as the proportion of patients with ORR and will be accompanied by a 95% 
confidence interval. 
  
All observed toxicities will be tabulated by type and grade.  All remaining secondary aims will be 
assessed with descriptive statistics and graphical displays to evaluate changes in outlined serum 
and bone marrow markers between pre- and post-treatment.  A paired t-test will be used to 
examine differences pre- and post-treatment.   
 
10.3 ACCRUAL  
Total accrual targets for this study are 32 with flexibility based on enrollment in phase I of the 
study. This study is planned as a 2-institution study, University of Nebraska Medical Center 
being the lead site, and MD Anderson Cancer Center a secondary site. Based on prior phase 
I and II studies at both sites, in a similar patient population, we estimate that 3 patients will 
be accrued every two months, suggesting that a total of 12-18 months will be needed to meet 
the sample size.   
 
 
10.4 Stopping Rules 
 
A response rate of 5% or less will be considered as clinically insignificant, while a response rate 
of 25% will be considered as clinically significant. With alpha= 0.05 and power of 0.80, the 
Simon optimal 2-stage design requires minimum enrollment of 9 patients in the first stage. The 
hypothesis will be rejected and enrollment will cease if no response is seen in the 9 patients. If 
at least 1 response is seen in the first 9 patients, another 14  patients will be accrued, for a total 
of 17 evaluable patients. At the end of the trial, the drug will be rejected if no more than 2 
responses are seen in the total of 17 evaluable patients. 
 
Cabozantinib will be taken in 20-mg capsules to reach the target dose levels as determined during 
the phase I and phase II portions of the study. This therapy will be continued without a cap on the 
number of allowed cycles, unless one of the following occurs: 
 Disease progression after two cycles or later of therapy 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 Patient becomes pregnant 
 Patient loses the ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of a psychiatric or physical illness 
 Patient achieves complete remission (CR), and the patient and investigator feel that 
discontinuation of cabozantinib is in the patient’s best interests, or 


 
 
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 Patient achieves a level of response that qualifies him or her for another therapy, such as 
high dose therapy with autologous stem cell transplantation. 
 
10.5 ANALYSIS OF GENE EXPRESSION PROFILING  
 
Our central hypothesis for the correlative laboratory studies is that inhibition of c-Met with 
cabozantinib will show anti-tumor efficacy especially in patients who have greater activation of 
the MU20/c-Met pathway at baseline, as determined by genomic and flow cytometry approaches.   
 
10.5.1 DATA PREPROCESSING 
 
For gene expression data, we will apply appropriate normalization methods for the expression 
profiles, which include quantile normalization77 and locally weighted scatterplot smoothing78, in 
order to make analyses comparable across arrays.  We shall use robust quantification methods 
such as the robust multichip analysis79 to produce a set of expression measurements, which will 
be used for subsequent downstream statistical analysis.   
 
10.5.2 DATA ANALYSIS 
 
To assess differential expression, we will use t-tests or Mann-Whitney tests if appropriate.  When 
there are more than two groups, an ANOVA (or non-parametric Kruskall-Wallis ANOVA) model 
will be used to test for biomarker expression differences among groups.  The significance 
threshold will be chosen based on standard methods that have been developed to adjust for 
multiple testing for such univariate tests; for example, bounding the false discovery rate (FDR)80 
using either Significance Analysis of Microarrays (SAM)81 or Beta-Uniform Mixture (BUM)82 
models. 
 
10.5.3 PATHWAY ANALYSIS 
 
The candidate signatures identified in the analysis associated with treatment/disease groups will 
be uploaded into the Ingenuity Pathway Analysis Application (IPA) for pathway analysis.  
Ingenuity's knowledge base is a repository of molecular interactions, regulatory events, gene-to-
phenotype associations, and chemical knowledge that provides the building blocks for pathway 
construction.  The pathways associated with treatment that are identified by the IPA software are 
ranked according to p-values.  The p-values are calculated by Fisher’s exact test, and can be 
adjusted to account for multiple testing using the methods outlined above. 
 
10.6 ANALYSIS OF SYMPTOM BURDEN AND QUALITY OF LIFE STUDIES 
 
The current study will examine the impact of therapy on each patient’s symptom burden using the 
MDASI-MM tool, and about each patient’s quality of life using the EORTC QLQ-C30 and QLQ-
MY20 tools.  Since studies using these tools in multiple myeloma patients treated with 
cabozantinib have not previously been performed, we are unable at this time to predict the impact 
of this agent on these parameters.  Therefore, we hope to collect pilot data in the course of this 
protocol which would be hypothesis generating, and which could be confirmed in future, larger, 
possibly randomized trials.  As a result, these studies are exploratory in nature, and their results 
will be examined using descriptive statistics. 
 
10.7 REPORTING AND EXCLUSIONS 
 


 
 
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10.7.1 EVALUATION OF TOXICITY 
 
All patients will be evaluable for toxicity from the time of their first treatment with cabozantinib. 
 
10.7.2 EVALUATION OF RESPONSE 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who received 
no study medication) should be included in the main analysis of the response rate. Those patients 
who do not receive a single dose of the investigational drug will be replaced in this trial with new 
patients.  Patients in response categories 4-9 should be considered to have a treatment failure 
(disease progression).  Thus, an incorrect treatment schedule or drug administration does not 
result in exclusion from the analysis of the response rate.   
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.).  However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.  The 95% confidence intervals should also be provided.  
 
 
11.0 Records to be Kept 
 
Information regarding the actual treatments, adverse effects, radiographic and laboratory 
information, and pathology are to be recorded on appropriate forms. See attached Data forms. 
De-identified source documents which support data entered must be provided to the sponsor by 
mail, fax, or electronic means for centralized compliance monitoring. Serious adverse events, 
when noted, will be recorded on site via the standard serious adverse effects form.   Adverse 
event lists, guidelines, and instructions for AE reporting can be found in Section 9.0 (Adverse 
Events: List and Reporting Requirements). 
 
11.1 Quality Assurance 
 
Complete records must be maintained in a research chart on each patient treated on the 
protocol. These records should include primary documentation (e.g., lab. report slips, X-ray 
reports, scan reports, pathology reports, physician notes, etc.) which confirm that:  
- The patient met the eligibility criteria.  
- Signed informed consent was obtained prior to treatment.  
- Treatment was given according to protocol (dated notes about doses given 
& reasons for any dose modifications).  
- Toxicity was assessed according to protocol (laboratory report slips, etc.).  


 
 
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- Response was assessed according to protocol (x-ray, scan, lab reports, 
dated notes on measurements & clinical assessment, as appropriate).  
 
 
Note:  All adverse events that have occurred on the study must be reported via the monitoring 
method identified above. 
 
11.2 Forte Electronic Data Capturing (EDC) System  
 
Data will be stored electronically for this study on the Forte secure server.  Data forms will not 
differ from the paper versions with the exception of an electronic format containing the UNMC 
Fred & Pamela Buffett Cancer Center and Forte logo. 
 
Forte EDC provides for remote data collection that meets FDA 21 CFR Part 11 requirements as 
well as HIPAA and other regulatory requirements designed to enhance data security and protect 
patient confidentiality. Authorized users log into Forte through a secure connection and must 
provide a valid username, password, and database ID.  This data may be made available to the 
public at large. 
 
 
 
 


 
 
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12.0 Patient Consent 
 
12.1 Human Subjects Research Protection Training 
All personnel involved in this research project will have completed the OHRP-approved 
computer based training course on the Protection of Human Research Subjects. All clinical 
and correlative research included in this application will have approval by the institutional 
review board.  
 
12.2 Study Population 
Subjects are from all socio-economic groups and will be entered into the study without bias 
with respect to gender or race. Attempts will be made to recruit minorities. No vulnerable 
subjects will be included in the study. 
 
12.3 Sources of Material 
Pathology material will be reviewed, and the diagnosis confirmed by each site’s Pathology 
department as outlined in protocol.   
 
12.4  
Recruitment and Informed Consent  
Subjects who are referred to the Nebraska Medical Center (NMC) / UNMC, or other IRB 
approved participating sites (MD Anderson), with relapsed and refractory (RR) multiple 
myeloma (MM) who have lost response to carfilzomib may be eligible for this study. 
These potential subjects will be informed of the nature of this study, and will be asked to 
participate on a voluntary basis after informing them of the possible risks and benefits of the 
study. A number of public registries may be accessible to health care providers and 
prospective subjects as listed below.  
National Library of Medicine - http://clinicaltrials.gov (NCT03201250) 
National Cancer Institute - http://www.cancer.gov (NCI--2017-02024)  
 
12.5 Subject Competency 
Subjects will be eligible to participate in the study only if they are competent to give informed 
consent. A subject that the investigators judges to be incompetent will not be enrolled. 
 
12.6 Process of Informed Consent 
If the patient chooses to be a participant in this study informed consent will be  obtained by 
the investigators. The study and procedures involved including the risks will be explained in 
detail to each subject. It will be clearly explained to the subject that this is a research study 
and that participation is entirely on a voluntary basis. Subjects will be given the option to 
discuss the study with a family member, friend, counselor or, another physician. The 
participating investigators will be available to discuss the study with them. 
 
12.7 Subject/Representative Comprehension 
When the process of informed consent is completed, the subject will be asked to state in 
his/her own words the purpose of the study, the procedures that will be carried out, potential 
risk, potential benefits to the subject, the alternatives and the right to withdraw from the 
study. If there are any indications that a given subject's comprehension is anything less than 
accurate, the points of confusion will be discussed and clarified. 
 
12.8 Information Purposely Withheld.  
 The results of the tests done solely for research purposes will not be disclosed to the 


 
 
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subject. No other information will be purposely withheld from the subject.   
 
12.9 Potential Benefits of the Proposed Research to the Subjects 
It is anticipated that the use of the protocol chemotherapy in this patient population may help 
control the disease. There are risks associated with chemotherapy, but the risk to benefit 
ratio is considered acceptable for patients with cancer. 
 
12.10 Potential Benefits to Society 
Information obtained from this study may help other patients by contributing to the 
knowledge of the biology of cancers, and to understand the potential clinical benefit of this 
regimen. 
 
12.11 Potential Risks 
The use of cytototoxic chemotherapy are associated with numerous potential risks. 
Combined chemotherapy is considered a valid treatment option for patients with advanced 
cancers. It is believed the treatment option outlined in the study will not pose significant 
additional risks compared to conventional treatment. 
 
12.12 Therapeutic Alternatives 
If subjects choose not to participate in this study they may elect to receive standard therapy 
as per their primary oncologist, which may include other chemotherapy drugs, radiation, 
surgery, or a combination of these approaches. The treatment recommendations may or 
may not be similar to treatment as described in this protocol. 
 
12.13 Risk/Benefit Relationship 
Although there are inherent risks involved because of the use of chemotherapy, the risk is 
considered to be acceptable in the setting of cancer. 
 
12.14 Consent Form Documents 
The consent document used in this study will include the adult consent document.  
 
 
 
13. 
 REFERENCES 
 
1. 
Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111(6):2962–72.  
2. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA. Cancer J. Clin. 60(5):277–
300.  
3. 
Silverberg E. Cancer statistics, 1983. CA. Cancer J. Clin. 33(1):9–25.  
4. 
Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with 
thalidomide and its derivatives. J. Clin. Oncol. 2003;21(23):4444–54.  
5. 
Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. 
Leukemia. 2009;23(11):1964–79.  
6. 
Harousseau J-L, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction 
treatment prior to autologous stem cell transplantation in patients with newly diagnosed 
multiple myeloma: results of an IFM phase II study. Haematologica. 2006;91(11):1498–
505.  
7. 
Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, 
doxorubicin and dexamethasone) for previously untreated patients with multiple 
myeloma. Br. J. Haematol. 2005;129(6):755–62.  


 
 
UNMC IRB #434-17 Protocol Version 5.4 Dated 04-20-21 
Page 79 of 105 
 
8. 
Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with 
thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology. 
2007;12(3):235–9.  
9. 
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose 
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for 
newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet. 
Oncol. 2010;11(1):29–37.  
10. 
San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and 
prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 2008;359(9):906–
17.  
11. 
Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide 
in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J. 
Clin. Oncol. 2009;27(22):3664–70.  
12. 
Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with 
multiple myeloma in 2006-2010. Haematologica. 2009;94(2):270–5.  
13. 
Kastritis E, Zervas K, Symeonidis A, et al. Improved survival of patients with multiple 
myeloma after the introduction of novel agents and the applicability of the International 
Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG). 
Leukemia. 2009;23(6):1152–7.  
14. 
Wang M, Delasalle K, Feng L, et al. CR represents an early index of potential long 
survival in multiple myeloma. Bone Marrow Transplant. 2010;45(3):498–504.  
15. 
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory 
multiple myeloma. N. Engl. J. Med. 1999;341(21):1565–71.  
16. 
Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent 
lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 
2009;114(4):772–8.  
17. 
Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed 
or refractory multiple myeloma. N. Engl. J. Med. 2007;357(21):2123–32.  
18. 
Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed 
multiple myeloma in North America. N. Engl. J. Med. 2007;357(21):2133–42.  
19. 
Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor 
PS-341 in patients with refractory hematologic malignancies. J. Clin. Oncol. 
2002;20(22):4420–7.  
20. 
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, 
refractory myeloma. N. Engl. J. Med. 2003;348(26):2609–17.  
21. 
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose 
dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 2005;352(24):2487–98.  
22. 
Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized Phase III Study of Pegylated 
Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed 
or Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression. J. 
Clin. Oncol. 2007;25(25):3892–3901.  
23. 
Kumar S, Larson DR, Therneau TM, Kyle RA GP. Natural history of relapsed multiple 
myeloma. Blood 2002;100(11)598a, Abstr. 2352. .  
24. 
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple 
myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international 
myeloma working group study. Leukemia. 2012;26(1):149–57.  
25. 
Weinstein IB. Cancer. Addiction to oncogenes--the Achilles heal of cancer. Science. 
2002;297(5578):63–4.  
26. 
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and 
more. Nat. Rev. Mol. Cell Biol. 2003;4(12):915–25.  
27. 
Jiang WG, Hiscox SE, Parr C, et al. Antagonistic effect of NK4, a novel hepatocyte 


 
 
UNMC IRB #434-17 Protocol Version 5.4 Dated 04-20-21 
Page 80 of 105 
 
growth factor variant, on in vitro angiogenesis of human vascular endothelial cells. Clin. 
Cancer Res. 1999;5(11):3695–703.  
28. 
Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met 
kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor 
activity in vivo. Cancer Res. 2003;63(21):7345–55.  
29. 
Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced 
signaling through adapter proteins. Oncogene. 2000;19(49):5582–9.  
30. 
Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and 
melanoma oncogene. Trends Mol. Med. 2006;12(9):406–14.  
31. 
McGill GG, Haq R, Nishimura EK, Fisher DE. c-Met expression is regulated by Mitf in the 
melanocyte lineage. J. Biol. Chem. 2006;281(15):10365–73.  
32. 
Exelixis I 2012. COMETRIQTM (cabozantinib) Package Insert.  
33. 
Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 
inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. 
Cancer Ther. 2011;10(12):2298–308.  
34. 
Smolen GA, Sordella R, Muir B, et al. Amplification of MET may identify a subset of 
cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. 
Proc. Natl. Acad. Sci. U. S. A. 2006;103(7):2316–21.  
35. 
Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem 
duplication in patients with acute myeloid leukemia (AML) adds important prognostic 
information to cytogenetic risk group and response to the first cycle of chemotherapy: 
analysis of 854 patients from the United King. Blood. 2001;98(6):1752–9.  
36. 
Munshi N, Jeay S, Li Y, et al. ARQ 197, a novel and selective inhibitor of the human c-
Met receptor tyrosine kinase with antitumor activity. Mol. Cancer Ther. 2010;9(6):1544–
53.  
37. 
Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine 
kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol. 
2011;29(19):2660–6.  
38. 
Cabanillas ME, Brose MS, Holland J, Ferguson KC, Sherman SI. A phase I study of 
cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid. 
2014;24(10):1508–14.  
39. 
Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate 
cancer: results of a phase II randomized discontinuation trial. J. Clin. Oncol. 
2013;31(4):412–9.  
40. 
Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary 
thyroid cancer. J. Clin. Oncol. 2013;31(29):3639–46.  
41. 
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced 
Renal-Cell Carcinoma. N. Engl. J. Med. 2015;373(19):1814–23.  
42. 
Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome. Cancer Res. 2007;67(13):6383–91.  
43. 
 Blood (ASH Annual Meeting Abstracts). Nov 2008; 112 2657. .  
44. 
 Blood (ASH Annual Meeting Abstracts). Nov 2008; 112 2765. .  
45. 
Herndon TM, Deisseroth A, Kaminskas E, et al. U.s. Food and Drug Administration 
approval: carfilzomib for the treatment of multiple myeloma. Clin. Cancer Res. 
2013;19(17):4559–63.  
46. 
Cvek B. Proteasome inhibitors. Prog. Mol. Biol. Transl. Sci. 2012;109:161–226.  
47. 
Spicka I. Advances in multiple myeloma therapy during two past decades. Comput. 
Struct. Biotechnol. J. 2014;10(16):38–40.  
48. 
Kurtin SE, Bilotti E. Novel agents for the treatment of multiple myeloma: proteasome 
inhibitors and immunomodulatory agents. J. Adv. Pract. Oncol. 2013;4(5):307–21.  
49. 
Murray MY, Auger MJ, Bowles KM. Overcoming bortezomib resistance in multiple 


 
 
UNMC IRB #434-17 Protocol Version 5.4 Dated 04-20-21 
Page 81 of 105 
 
myeloma. Biochem. Soc. Trans. 2014;42(4):804–8.  
50. 
Oerlemans R, Franke NE, Assaraf YG, et al. Molecular basis of bortezomib resistance: 
proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 
protein. Blood. 2008;112(6):2489–99.  
51. 
Lü S, Yang J, Chen Z, et al. Different mutants of PSMB5 confer varying bortezomib 
resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. 
Exp. Hematol. 2009;37(7):831–7.  
52. 
Markovina S, Callander NS, O’Connor SL, et al. Bone marrow stromal cells from multiple 
myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma 
cells. Mol. Cancer. 2010;9:176.  
53. 
Barrera LN, Rushworth SA, Bowles KM, MacEwan DJ. Bortezomib induces heme 
oxygenase-1 expression in multiple myeloma. Cell Cycle. 2012;11(12):2248–52.  
54. 
Rushworth SA, Zaitseva L, Murray MY, et al. The high Nrf2 expression in human acute 
myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. Blood. 
2012;120(26):5188–98.  
55. 
Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an 
update. Nat. Rev. Cancer. 2012;12(3):159–69.  
56. 
Kuhn DJ, Berkova Z, Jones RJ, et al. Targeting the insulin-like growth factor-1 receptor to 
overcome bortezomib resistance in preclinical models of multiple myeloma. Blood. 
2012;120(16):3260–70.  
57. 
Dasmahapatra G, Patel H, Dent P, et al. The Bruton tyrosine kinase (BTK) inhibitor PCI-
32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell 
lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to 
bortezomib. Br. J. Haematol. 2013;161(1):43–56.  
58. 
Kirk CJ. Discovery and development of second-generation proteasome inhibitors. Semin. 
Hematol. 2012;49(3):207–14.  
59. 
Kortuem KM, Stewart AK. Carfilzomib. Blood. 2013;121(6):893–7.  
60. 
Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-
003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 
2012;120(14):2817–25.  
61. 
Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) 
study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or 
refractory multiple myeloma. Blood. 2012;119(24):5661–70.  
62. 
Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible 
inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple 
myeloma. Blood. 2007;110(9):3281–90.  
63. 
Ma W, Wang M, Wang Z-Q, et al. Effect of long-term storage in TRIzol on microarray-
based gene expression profiling. Cancer Epidemiol. Biomarkers Prev. 2010;19(10):2445–
52.  
64. 
Van Gelder RN, von Zastrow ME, Yool A, et al. Amplified RNA synthesized from limited 
quantities of heterogeneous cDNA. Proc. Natl. Acad. Sci. U. S. A. 1990;87(5):1663–7.  
65. 
Ahmann GJ, Chng WJ, Henderson KJ, et al. Effect of tissue shipping on plasma cell 
isolation, viability, and RNA integrity in the context of a centralized good laboratory 
practice-certified tissue banking facility. Cancer Epidemiol. Biomarkers Prev. 
2008;17(3):666–73.  
66. 
Davis RE, Staudt LM. Molecular diagnosis of lymphoid malignancies by gene expression 
profiling. Curr. Opin. Hematol. 2002;9(4):333–8.  
67. 
Lenz G, Wright GW, Emre NCT, et al. Molecular subtypes of diffuse large B-cell 
lymphoma arise by distinct genetic pathways. Proc. Natl. Acad. Sci. U. S. A. 
2008;105(36):13520–5.  
68. 
Stellrecht CM, Phillip CJ, Cervantes-Gomez F, Gandhi V. Multiple myeloma cell killing by 


 
 
UNMC IRB #434-17 Protocol Version 5.4 Dated 04-20-21 
Page 82 of 105 
 
depletion of the MET receptor tyrosine kinase. Cancer Res. 2007;67(20):9913–20.  
69. 
Phillip CJ, Stellrecht CM, Nimmanapalli R, Gandhi V. Targeting MET transcription as a 
therapeutic strategy in multiple myeloma. Cancer Chemother. Pharmacol. 
2009;63(4):587–97.  
70. 
Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer 
patients: the M.D. Anderson Symptom Inventory. Cancer. 2000;89(7):1634–46.  
71. 
Campagnaro E, Saliba R, Giralt S, et al. Symptom burden after autologous stem cell 
transplantation for multiple myeloma. Cancer. 2008;112(7):1617–24.  
72. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology. J. Natl. Cancer Inst. 1993;85(5):365–76.  
73. 
Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQ-C30 
(version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in 
head and neck patients. EORTC Quality of Life Group. Eur. J. Cancer. 
2000;36(14):1796–807.  
74. 
Cocks K, Cohen D, Wisløff F, et al. An international field study of the reliability and 
validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the 
quality of life of patients with multiple myeloma. Eur. J. Cancer. 2007;43(11):1670–8.  
75. 
Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and 
progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant. Br. J. Haematol. 1998;102(5):1115–23.  
76. 
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel 1. Blood. 2011;117(18):4691–5.  
77. 
Bolstad BM, Irizarry RA, Astrand M, Speed TP. A comparison of normalization methods 
for high density oligonucleotide array data based on variance and bias. Bioinformatics. 
2003;19(2):185–93.  
78. 
Yang YH, Speed T. Design issues for cDNA microarray experiments. Nat. Rev. Genet. 
2002;3(8):579–88.  
79. 
Irizarry RA, Bolstad BM, Collin F, et al. Summaries of Affymetrix GeneChip probe level 
data. Nucleic Acids Res. 2003;31(4):e15.  
80. 
Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in 
behavior genetics research. Behav. Brain Res. 2001;125(1-2):279–84.  
81. 
Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the 
ionizing radiation response. Proc. Natl. Acad. Sci. U. S. A. 2001;98(9):5116–21.  
82. 
Pounds S, Morris SW. Estimating the occurrence of false positives and false negatives in 
microarray studies by approximating and partitioning the empirical distribution of p-
values. Bioinformatics. 2003;19(10):1236–42.  
83.  
Simon, Richard. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled 
Clinical Trials. 1989; 10:1-10. 
84. 
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced 
renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 
trial. Lancet Oncol 2016;17:917–27. 
85. 
Nguyen, L, Holland, J, Ramies, D et al. Effect of Renal and Hepatic Impairment on the 
Pharmacokinetics of Cabozantinib. J. Clin Pharmacol. 2016; 56(9): 1130-40.   
86. 
Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to 
tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin 
Oncol. 2009;6(4):219-28. 
 


 
 
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14.0 Data Collection Forms 
 
Attached. 
 
 


 
 
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APPENDIX A: ELIGIBILITY CHECKLIST 
IRB# 434-17-FB 
Title: A Phase I/II Study of the c-Met Inhibitor Cabozantinib as a 
Targeted Strategy to Reverse Resistance to the Proteasome Inhibitor Carfilzomib 
in Refractory Multiple Myeloma 
 
 
Date 
Completed: 
 
Institution:  
Investigator: 
Subject ID:  
Checklist #: 
Protocol v5.2 
dated  08-23-19 
Inclusion Criteria:   
                
1. Patients must have been previously diagnosed with histologically or cytologically 
confirmed symptomatic multiple myeloma, which require the presence of all three of 
the following International Myeloma Working Group 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) 
o Hypercalcemia (corrected calcium > 2.75 mmol/L or 11.5 mg/dL); OR 
o Renal insufficiency attributable to myeloma (serum creatinine >1.9 
mg/dL); OR 
o Anemia; normochromic, normocytic with a hemoglobin value ≥2 g/dL 
below the lower limit of normal, or a hemoglobin or <10 g/dL; OR 
o Bone lytic lesions, severe osteopenia or pathologic fractures. (MRI, CT 
or PET/CT with > 1 focal lesions ≥5 mm in size) 
 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, as defined by at least one of the following: 
 Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease 
 Monoclonal 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, along with an abnormal free light chain 
ratio 
 
3. Patients prior lines of therapy f must be separated by the 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. 
 
4. Patients eligible for this trial will be those who have previously failed carfilzomib at 
any point either as a single agent, or carfilzomib in combination with dexamethasone, 
Yes   No  N/A 
 
[   ]    [   ] 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 2. 
 
 
 
 
 
 
 
 
[   ]    [   ] 3. 
 
 
 
 
 
 


 
 
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or carfilzomib in combination with dexamethasone and any of the following agents: 
revlimid, cyclophosphamide, pomalidomide, daratumumab or bendamustine. Given 
the potential for compounding/worsening toxicities with the addition of cabozantinib to 
carfilzomib, patients eligible for the trial will 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 (PD) 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 multiple 
myeloma in the following timeframes: 
 Chemotherapy, biological therapy, immunotherapy, monoclonal antibody 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 at least 6 weeks prior to starting 
cabozantinib 
 Autologous stem cell transplantation or autologous chimeric antigen receptor 
(CAR) T cell therapy at least 12 weeks prior to starting cabozantinib 
 Allogeneic stem cell transplantation or allogeneic CAR T cell 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 Nebraska), because no dosing or adverse 
event data are currently available on the use of cabozantinib in patients <19 years of 
age.  
 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; 
please see Appendix E) 
 
9. Patients must have evidence of adequate bone marrow reserves, as defined by the 
following: 
[   ]    [   ] 4. 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 6. 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 7. 
 
 
 
[   ]    [   ] 8. 
 
 
[   ]    [   ] 9. 
 
 


 
 
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_____ Absolute neutrophil count (ANC) ≥1,000 cells/mm3 without growth 
factors within 1 week of the initiation of treatment 
______ Total white blood cell count (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 (SGOT) and ALT (SGPT) ≤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: 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
 
72 x serum creatinine in mg/dL 
Male CrCl = (140 - age in years) x weight in kg x 1.00 
 
72 x serum creatinine in mg/dL 
Worsening urinary paraproteinemia will be considered in the context of IMWG disease 
response criteria on a monthly basis. 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 New York Heart Association (NYHA) class II, III, or IV congestive heart 
failure (please see Appendix F for the NYHA classification system) 
 Absence of uncontrolled angina or hypertension defined as sustained blood 
pressure (BP) > 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: 
o myocardial infarction; 
o unstable angina pectoris; 
o clinically-significant cardiac arrhythmias;  
o stroke (including transient ischemic attack (TIA), or other ischemic 
event);  
o thromboembolic event requiring therapeutic anticoagulation (Note: 
subjects with a venous filter (eg, vena cava filter) are not eligible for 
this study)  
 Absence of myocardial infarction in the previous 6 months 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 10. 
 
 
 
 
 
 
 
[   ]    [   ] 11. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 12. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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 Absence of clinically significant bradycardia, or other uncontrolled cardiac 
arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI) 
Common Terminology  
 Absence of history of congenital long QT syndrome 
 
13. Patients who have received radiation therapy must have completed this at least 
4 weeks prior to starting therapy with cabozantinib, with the following exceptions: 
 Local radiation therapy to enhance bone healing of a pathologic fracture may have 
been performed, as long as it was completed at least 2 weeks prior to starting 
cabozantinib 
 Local radiation therapy to treat post-fracture pain that is refractory to analgesics 
may have been performed, as long as it was completed at least 2 weeks prior to 
starting cabozantinib 
 
14. Patients who have undergone any recent major surgery must have done so at 
least 4 weeks prior to starting therapy with cabozantinib, with the following 
exceptions: 
 Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 
week prior to starting cabozantinib 
 Planned elective surgery unrelated to the patient’s diagnosis of multiple myeloma, 
such as hernia repair, may be allowed, at the discretion of the principle 
investigator, as long as it was performed at least 2 weeks prior to starting 
cabozantinib, and patients have recovered fully from this procedure 
 
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 cubic millimeter of blood, will be eligible.  
However, HIV positive patients on combination antiretroviral therapy will be ineligible, 
because of the potential for pharmacokinetic interactions with cabozantinib. 
 
16. Screen subjects prior to treatment whose baseline hepatitis B serologic status is 
unknown.  Subjects, who are chronic carriers of hepatitis B virus, please screen with 
hepatitis B DNA to exclude active viral replication and monitor hepatitis B DNA at 
regular intervals while on study. 
 
17.  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).  Male subjects must agree 
to not donate sperm for at least 90 days after the last dose of Carfilzomib.   
 
18.  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 (βHCG) or urine pregnancy test before receiving the first dose of 
cabozantinib 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 
 
 
 
 
 
[   ]    [   ] 13. 
 
 
 
 
 
 
 
 
[   ]    [   ] 14. 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 15. 
 
 
 
 
 
[   ]    [   ] 16. 
 
 
 
 
 
[   ]    [   ] 17. 
 
 
 
 
 
 
[   ]    [   ] 18. 
 
 
 
 
 
 
 


 
 
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treating physician immediately. Women of reproductive potential will be counseled to 
use effective contraceptive measures to prevent pregnancy during treatment with 
either cabozantinib or carfilzomib. Patients shall be advised not to take cabozantinib 
or carfilzomib treatment while pregnant or breastfeeding. If a patient wishes to 
restart breastfeeding after treatment, she will be advised to discuss the appropriate 
timing with her physician. 
 
19. 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. 
 
 
All of the above must be yes to be eligible 
 
 
 
 
 
 
 
[   ]    [   ] 19. 
 
Exclusion Criteria: 
 
1. Patients who are receiving any concurrent investigational agent with known or 
suspected activity against multiple myeloma, or those whose adverse events due to 
agents administered more than 4 weeks earlier have not recovered to a severity of 
grade 0 or grade 1. 
 
2. Patients who have known central nervous system involvement with multiple 
myeloma will 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. 
 
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. Cabozantinib is metabolized by CYP3A4.  The metabolism and consequently 
overall pharmacokinetics of cabozantinib could be altered by inhibitors and/or 
inducers or other substrates of CYP3A4. It is recommended that chronic concomitant 
treatment with strong CYP3A4 inhibitors (eg, phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital, and St. John’s Wort) or inducers 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 enrolment. While mild 
inhibitors/inducers of these cytochrome P450 isoenzymes are not specifically 
excluded, investigators should be aware that cabozantinib exposure may be altered 
by the concomitant administration of these drugs and avoidance is also 
recommended.  Lists including medications and substances known or with the 
potential to interact with CYP3A4 are provided in Appendix G. 
 
6. Uncontrolled or ongoing/active infection. Due to side effect profile of cabozantinib, 
patients with the following history will also not be eligible for the trial: patients with a 
recent history of hemorrhage or hemoptysis; patients with dehiscence or wound 
healing complications requiring medical intervention; patients with severe 
 
 
[   ]    [   ]1. 
 
 
 
 
[   ]    [   ]2. 
 
 
 
 
[   ]    [   ]3. 
 
 
 
[   ]    [   ]4. 
 
 
[   ]    [   ]5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ]6. 
 
 
 


 
 
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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 are excluded from this study because cabozantinib is 
a tyrosine kinase inhibitor 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 cabozantinib, breastfeeding should be 
discontinued if the mother is treated with cabozantinib. 
 
8. Patients with non-secretory multiple myeloma, active plasma cell leukemia, defined 
as either having 20% of peripheral white blood cells comprised of CD138+ plasma 
cells, or an absolute plasma cell count of 2 x 109/L, known amyloidosis, or known 
POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes). 
 
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, due to the difficulty that would be faced in assessing the attribution 
of any events of hepatic toxicity while on cabozantinib therapy 
 
11. Patients with a “currently active” second malignancy, other than non-melanoma 
skin cancer and carcinoma in situ of the cervix, should not be enrolled.  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.  In addition, 
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 will be eligible.  Finally, patients who are on hormonal therapy 
for a history of either prostate cancer or breast cancer may enroll, if there has been 
no evidence of disease progression during the previous three 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: 
o 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 
 
 
 
 
[   ]    [   ]7. 
 
 
 
 
 
 
[   ]    [   ]8. 
 
 
 
 
 
[   ]    [   ]9. 
 
 
[   ]    [   ]10.  
 
 
 
[   ]    [   ]11. 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ]12.  
 
[   ]    [   ] 13.  
 
 
 
 
 
 
[   ]    [   ] 14.  
 
 
 
 
 
 


 
 
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o Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal 
abscess within 6 months before  randomization, 
Note: Complete healing of an intra-abdominal abscess must be confirmed 
prior to randomization 
 hemoptysis of ≥ 0.5 teaspoon (2.5ml) 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. 
 Patient who have developed or have had history of pulmonary hemorrhage 
while on carfilzomib will be excluded (fatal pulmonary hemorrhage has been 
observed with carfilzomib).  
 
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.  Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 14 days before first dose of study treatment. 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two 
additional ECGs at intervals of approximately 3 min must be performed 
within 30 min after the initial ECG, and the average of these three 
consecutive results for QTcF will be used to determine eligibility.  
 
19.  Inability to swallow intact tablets 
 
20. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) 
test ≥ 1.3 × 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);  
 
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 
1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted if started > 6 
months prior to randomization. LMWH used as therapeutic anticoagulation may increase observed 
PTT levels in subjects.  . Anticoagulation with therapeutic doses of LMWH is allowed in subjects 
without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 
24 weeks before randomization, and who have had no complications from a thromboembolic event 
or the anticoagulation regimen. 
22. Subjects who have Carfilzomib-related posterior reversible encephalopathy 
syndrome (PRES) and thrombotic microangiopathy (TMA) should not be 
challenged with Carfilzomib.   
 
All of the above must be no to be eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[   ]    [   ] 15.  
 
[   ]    [   ] 16.  
 
[   ]    [   ] 17.  
 
 
 
[   ]    [   ] 18.  
 
 
 
 
[   ]    [   ] 19.  
 
[   ]    [   ] 20.  
 
 
[   ]    [   ] 21.  
 
 
 
 
 
 
 
 
 
[   ]    [   ] 22.  
 
Eligibility:      [    ]  Patient satisfies all criteria.  
                     [    ]  Patient not formally eligible, but admitted to study because (state reason);  
 


 
 
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Patient Initials:  ______________MR #______________DOB ______________ 
 
ELIGIBILITY reviewed and confirmed  
Site Investigator Signature _______________________Date_____________        
 
Appendix B: MDASI - MM TOOL 
 
 
 
 
 


 
 
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APPENDIX C: EORTC QLQ-C30 TOOL 
 
 
 
 
 


 
 
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APPENDIX D: EORTC QLQ-MY20 TOOL 
 
 
 
 
 
 
 


 
 
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APPENDIX E: ECOG PERFORMANCE STATUS SCALE 
 
 
 
 
 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 


 
 
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APPENDIX F: NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION 
SYSTEM 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX G: LIST OF POTENTIAL DRUG INTERACTIONS 
 
 
When drugs classified as ‘substrates’ are co-administered with cabozantinib, there is the potential for 
higher concentrations of the ‘substrate.’  When cabozantinib is co-administered with compounds 
classified as ‘inhibitors,’ increased plasma concentrations of cabozantinib is the potential outcome.  The 
co-administration of ‘inducers’ would potentially lower plasma cabozantinib concentrations. 
 
 
 


 
 
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CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib (1) 
Delavirdine 
Diazepam 
Dihydroergotamine  
Diltiazem  
Disopyramide  
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine  
Itraconazole 
Ketamine  
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole  
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
 


 
 
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CYP3A4 Inhibitors 
Strong inhibitors:  
indinavir  
nelfinavir  
ritonavir  
clarithromycin  
itraconazole  
ketoconazole  
nefazodone  
saquinavir  
suboxone  
telithromycin  
cobicistat  
boceprevir  
mibefradil  
telaprevir  
troleandomycin  
posaconazole  
 
Moderate inhibitors: 
aprepitant 
amprenavir 
amiodarone 
atazanavir 
ciprofloxacin 
crizotinib 
darunavir/ritonavir 
dronedarone 
erythromycin 
diltiazem 
fluconazole 
grapefruit juice 
Seville orange juice 
verapamil 
voriconazole 
imatinib 
 
Weak inhibitors: 
cimetidine 
fluvoxamine 
 
All other inhibitors: 
chloramphenicol 
delaviridine 
diethyl-dithiocarbamate 
gestodene 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
 
When drugs classified as ‘substrates’ are co-administered with cabozantinib, there is the 
potential for higher concentrations of the ‘substrate’. When cabozantinib is co-administered with 
compounds classified as ‘inhibitors’, increased plasma concentrations of cabozantinib is the 
potential outcome. The co-administration of ‘inducers’ would potentially lower plasma 
cabozantinib concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp 
Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
 
(1)  Wang et al. (2004). Clin Pharmacol Ther. 75:191-197 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
(4)  Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
 
 
 
 
 
 


 
 
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APPENDIX H: STUDY MEDICATION DIARY 
 
CYCLE_______________ Date__________ 
Study ID: ____________ 
 
Your prescribed dose of cabozantnib is _________________. Number of Pills Dispensed: _________________ 
   If you miss a dose please add the comment “missed dose” on the corresponding date.  Dose should not be replaced. 
   If your Study Doctor has asked you to change your dose, please add the new dosage on the corresponding date. 
  Return all study drug bottles, any unused drug and completed diaries to the Study Coordinators at the study site. 
 
Cabozantinib tablets should be taken by mouth, at least 2 hours before and at least 1 hour after eating.  
Tablets should be taken with water and swallowed whole. 
 
 
 
You are to take your study medication as follows: 
# of Pills 
# of time(s) per day 
Duration: days/weeks/months 
Special instruction 
 
 
 
 
 
Month ___________ 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
# of pills_______ 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
# of pills_______ 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
# of pills_______ 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
# of pills_______ 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
# of pills_______ 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time ____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
# of pills_______ 
 
Time _____am/pm 
 
Notes: 
 
 


 
 
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Drug Diary for Oral Dexamethasone: 
 
Record Date and 
Time taken  
Record Dose of 
Dexamethasone taken 
If dose of any drug was missed or changed, 
provide a reason 
 
mg  
 
mg  
 
mg  
 
mg  
 
mg  
 
mg  
 
mg  
 
mg  
 
 


 
 
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APPENDIX I: Child-Pugh Classifications 
 

ICF_001.pdf: 
PT NAME:   
MR#: 
CONSENT FORM
IRB PROTOCOL # 434-17-FB
  Page 1 of 21
ADULT CONSENT - CLINICAL BIOMEDICAL
Phase I Consent
Title of this Research Study
A Phase I/II Study of the c-Met Inhibitor Cabozantinib as a Targeted Strategy to
Reverse Resistance to the Proteasome Inhibitor Carfilzomib in Refractory Multiple
Myeloma
Invitation
You are invited to take part in this research study. You have a copy of the following,
which is meant to help you decide whether or not to take part:
Informed consent form
"What Do I need to Know Before Being in a Research Study?"
The Rights of Research Subjects
Why are you being asked to be in this research study?
You are being asked to be in this study because you are 19 years of age or older and
have multiple myeloma (MM) that has either come back or has not responded to
treatment. You have also already progressed after prior treatment with Carfilzomib.
Up to 10 patients may be enrolled at UNMC/Nebraska Medicine. It is planned that up
to 32 patients total will be enrolled in the study at UNMC and MD Anderson.
If you are pregnant, nursing an infant, or plan to become pregnant during this study,
you may not be in this study.
What is the reason for doing this research study?
The purpose of Phase I of this research study is to find the highest dose of
cabozantinib that can be given safely in combination with carfilzomib. To do this, a
small number of subjects are given a low dose of the investigational medicine, and
side effects are noted. If the side effects are tolerable, then the next group will
receive a higher dose, and this will be repeated with successive groups until some
subjects experience certain side effects. The particular dose you receive will depend
on when you enter the study. The dose you receive will not increase.
Both drugs are FDA approved, but the combination of the two is experimental.
Carfilzomib is FDA approved to block cancer cells from repairing themselves in
patients with Mulitple Myeloma (MM). Carfilzomib is designed to keep cancer cells
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from repairing themselves. If the cancer cells cannot repair themselves, this may
cause them to die.
Cabozantinib is FDA approved and commercially available for the treatment of
medullary thyroid cancer. Cabozantinib is designed to stop the growth of cancer cells
who signal through the c-Met signaling pathway in which might be over-active in MM
and has become resistant to carfilzomib. This may reduce or stop the growth of
cancer cells. Its use in this study is investigational.
What will be done during this research study?
We do not know the highest dose of cabozantinib that is safe. Phase I of this study is
to determine the safest dose of cabozantinib in combination with carfilzomib. Different
doses of cabozantinib will be given to see if there are good or bad side effects on you
and your cancer.
To do this, a small number of subjects (3-6 patients per group) are given a low dose
of the investigational medicine, and side effects are noted. If the side effects are
tolerable, then the next group will receive a higher dose, and this will be repeated
with successive groups until some subjects experience certain side effects. The
particular dose you receive will depend on when you enter the study.
You will be made aware of what dose of cabozantinib your are receiving.
All subjects in this study will received a fixed dose of carfilzomib throughout the
study.
The study investigator will review your medical history and current medications to
determine if you might be eligible to participate in the study. If you choose to sign this
informed consent form, you will continue with the screening process. Many of the
tests may be the same as those you have already completed for the diagnosis of
your multiple myeloma.
Screening Visit
Signing this consent form does not mean that you will be able to take part in this
study. You will have screening tests to help the investigator decide if you are eligible
to take part in this study. The screening process may take place over a period of up
to 28 days. These may take more than one visit and will include the following:
You will have a complete physical exam, including measurement of your
height, weight, and vital signs (heart rate, blood pressure, and temperature).
You will have a specific exam of your mouth (oral assessment)
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Your medical history will be recorded.
Your actual health status and your well-being will be assessed. This is called
a performance status assessment.
You will have tests to check your heart function. These tests include an
electrocardiogram (ECG) and echocardiogram (ECHO).
Blood (about 2 tablespoons) and urine will be collected for routine tests. If
urine is collected, you will be asked to collect your urine over a 24-hour
period. You will be given a container for collection and will be told how to use
and store it.
If you are able to become pregnant, your blood or urine will also be
used for a pregnancy test. To take part in this study, you must not be
pregnant.
Blood (about 1 teaspoon) and/or urine will be collected to check the status of
the disease, level of antibodies and your immune system.
You will have a bone marrow aspiration and/or biopsy to check the status of
the disease. To collect a bone marrow aspirate/biopsy, an area of the hip is
numbed with anesthetic, and a small amount of bone marrow and/or bone is
withdrawn through a large needle.
You will have x-rays of your entire body to check for any bone fractures or
tumors of the bone.
You may have a CT scan or MRI scan to determine the size, locations of you
cancer, if they are clinically indicated and have not already been done.
In addition, we will draw a blood sample for research testing (2 teaspoons)
Prior to starting study drug, medication diaries will be given to you. A member
of the study staff will explain how to use the diaries. You will enter information
about carfilzomib and cabozantinib that you take at home. You must bring the
diaries with you whenever you come to the study clinic.
The study investigator will discuss the screening test results with you. If the screening
tests show that you are not eligible to take part in the study you will not be enrolled.
Other options will be discussed with you.
Study Drug Administration
Every study cycle will be 28 days.
You will take cabozantinib pills by mouth on Days 1-28 of each 28-day study cycle.
You will be given medication diaries. You should inform the study investigator and/or
study staff of any missed doses of cabozantinib.
You will be asked to return any unused cabozantinib and empty bottles to the clinic at
each study visit.
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You will receive carfilzomib by vein over 10 minutes on Days 1, 2, 8, 9, 15, and 16 of
each cycle.
You will be given a Drug Information sheet in addition to this consent form.
As part of pre-treatment medications, you will receive dexamethasone by mouth or by
vein on Days 1,8,15 and 22 (for patients 75 years old or older you will receive
dexamethasone by mouth or by vein on Days 1,2,8,9,15,16,22 and 23).
Study Visits
At all study visits, you will be asked about any other drugs you may be taking and
about any side affects you may be having.
Prior to/On Day 1 of each cycle (If some of these tests were performed within 3
days before Cycle 1, they will not need to be done on Day 1 of Cycle 1):
You will have a physical exam, including measurement of your weight and
vital signs.
You will be asked about any side effects and other medication you have
used.
Your actual health status and your well-being will be assessed. This is called
a performance status assessment
You will complete a questionnaires about your nerve function and quality of
life. Each of these questionnaires will take about 10 minutes to complete.
You will have an electrocardiogram (EKG) to check your heart function
Blood (about 2 tablespoons) will be drawn for routine tests.
Blood (about 1 teaspoon) and/or urine will be collected to check the status of
the disease. If urine is collected, you will be asked to collect your urine over a
24-hour period.
On Days 8 and 22 of Cycle 1:
Blood (about 2 tablespoons) will be drawn for routine tests.
On Day 15 of Cycle 1:
You will be have a brief physical exam, including measurement of vital signs.
You will be asked about any side effects and other medication you have
used.
Your actual health status and your well-being will be assessed. This is called
a performance status assessment.
You will complete a questionnaire about your performance status of the
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disease.
Blood (about 2 tablespoons) will be drawn for routine tests.
Blood (about 1 teaspoon) and/or urine will be collected to check the status of
the disease.
On Days 1 of Cycles 2-3 and beyond
The assessments listed above for Day 1 will be performed. Additionally:
Medication diaries will be reviewed and drug returns will be counted and new
diaries will be given to you
On Cycle 3 only, we will draw a blood sample for research testing (2
teaspoons)
On Cycle 3 only, you will have a bone marrow biopsy/aspiration to check the
status of the disease. Extra sample from the aspiration will be collected for
the research samples.
On Days 15 of Cycles 2-3, and then beyond:
You will complete a questionnaire about your performance status of the
disease
If at any point the study tests show that the disease has changed (gotten worse or
better), you may be asked to have additional imaging scans, blood and/or urine tests.
You may also have an additional bone marrow aspiration and biopsy. The
investigator will tell you more about any additional tests that need to be performed.
Length of Study
You may continue taking the study drugs for as long as the doctor thinks it is in your
best interest. You will no longer be able to take the study drugs if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.
Your participation on the study will be over once you have completed the End of
Treatment visit.
End of Treatment Visit
About 30 days after your last dose of study drugs, the following tests and procedures
will be performed:
You will have a physical exam, including measurement of your vital signs.
You will be asked about any side effects and other medication you have
used.
You will complete a questionnaire about your performance status of the
disease
You will complete a questionnaires about your nerve function and quality of
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life.
Blood (about 2 tablespoons) will be collected for routine tests.
Blood (about 1 teaspoon) and/or urine will be collected to check the status of
the disease. If urine is collected, you will be asked to collect your urine over a
24-hour period.
If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test. This test will be performed when you stop taking Cabozantinib and
again about 30 days later.
Data collection after End of Treatment
We will ask to continue to collect information from you about how you are doing and
effects of the study treatment on cancer following the end of study treatment.
What are the possible risks of being in this research study?
While on this study, you are at risk for side effects. These side effects will vary from
person to person. Many side effects go away shortly after treatment is stopped, but in
some cases side effects may be serious, long-lasting or permanent, and may even
result in hospitalization and/or death. Tell the study staff about any side effects you
may have, even if you do not think they are related to the study drugs.
The dose of the investigational medicine (cabozantinib) will be increased with each
successive group of subjects to see what dose causes side effects. Therefore,
depending on when you enter the study (which group you are in) you may experience
more or new side effects not seen with lower doses.
Effects of Cabozantinib (XL184) in Humans
When participating in clinical studies with an investigational drug, cancer patients
may experience side effects related to the drug. In studies of cabozantinib given
alone, side effects related to cabozantinib have been reported in patients with many
different types of cancer.
Side effects that occurred in less than 5% of patients but were considered medically
important or severe or life-threatening and rarely fatal are listed in the next table.
These events occurred in studies of cabozantinib given alone. If you are at the
clinical site and notice any signs or symptoms of the side effects listed below, check
with the staff in the clinic immediately; if you are no longer at the clinical site, call your
doctor or go immediately to the nearest hospital.
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Side Effects That Occurred in More than 20% of Cancer Patients Treated with
Cabozantinib
high blood pressure
fatigue
weakness
changes in hair color
hand-foot syndrome
(palms of
hands/soles of feet
having pain,
swelling, and
blistering
skin rash
high blood levels of
fat (possible heart
disease and/or
stroke)
high blood sugar
(possible diabetes)
abnormal salts,
minerals, and/or
acids in the blood
(possible weakness,
swelling, fatigue, low
blood pressure,
organ failure, heart
problems, changes
in mental status,
and/or seizure)
underactive thyroid
gland (possible
weight gain, heart
failure, and/or
constipation)
mouth blisters/sores
(possible difficulty
swallowing)
mouth pain
abnormal taste
loss of appetite
weight loss
diarrhea
nausea
abdominal pain
constipation
vomiting
low blood counts
(red/white/platelets)
abnormal liver or
bone tests (possible
liver damage and/or
yellowing of the skin
and/or eyes)
abnormal kidney test
(possible kidney
damage)
Cabozantinib may cause low blood counts (red blood cells, white blood cells, and/or
platelets).
A low white blood cell count increases your risk of infection (such as
pneumonia and/or severe blood infection). Infections may occur anywhere
and become life-threatening. Symptoms of infection may include fever, pain,
redness, and difficulty breathing.
A low platelet count increases your risk of bleeding (such as nosebleeds,
bruising, stroke, and/or digestive system bleeding). You may need a platelet
transfusion.
A low red blood cell count (anemia) may cause shortness of breath and/or
fatigue. You may need a blood transfusion.
Side Effects That Occurred in 3 to 20% of Cancer Patients Treated with
Cabozantinib
blood clots in the
veins
low blood pressure
(possible
hole in the stomach
or intestines
(possibly leaking
contents into the
abnormal sensation
(such as pins and
needles)
nerve damage
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Damage to the outermost surface of the eye
Inflammation and blockage of channels that carry bile from the liver
Severe swelling of the mouth, lips, tongue, eyes and throat, or difficulty
swallowing or breathing
Very high blood pressure that comes on suddenly and quickly and which can
lead to serious injury to the heart and brain
Effects of Carfilzomib in Humans
Carfilzomib may cause all, some, or none of the side effects listed below. These side
effects can be mild but could also be serious and some may even result in death.
There may also be unknown side effects from taking carfilzomib alone or with other
drugs you may be taking.
Carfilzomib each may cause low blood cell counts (red blood cells, platelets, and/or
white blood cells):
A low red blood cell count (anemia) may cause difficulty breathing and/or
fatigue. You may need a blood transfusion.
A low platelet count increases your risk of bleeding (such as nosebleeds,
bruising, stroke, and/or digestive system bleeding). You may need a platelet
transfusion.
A low white blood cell count increases your risk of infection (such as
pneumonia and/or severe blood infection). Infections may occur anywhere
and become life-threatening. Symptoms of infection may include fever, pain,
redness, and difficulty breathing.
Very Common (may affect more than 1 in 10 patients)
swelling of hands,
feet or ankles
headache
high blood pressure
shortness of breath
muscle spasms
fever
fatigue and
tiredness
nausea/vomiting
diarrhea
constipation
low blood cell counts
(red, platelets,
white)
respiratory tract
infections
pneumonia
decreased blood
levels of potassium
increased creatinine
levels
cough with phlegm
bronchitis
dizziness
weakness
numbness
difficulty sleeping
decreased appetite
back pain
joint pain
pain in limbs (hands
or feet)
Common (may affect up to 1 in 10 patients)
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fever associated
with low white blood
cell count
chest pain
heart attack
heart failure and
heart problems
including rapid
strong or irregular
heartbeat
chills
pain
stomach pain
indigestion
toothache
ringing in the ears
decreased blood
levels of sodium,
magnesium, protein,
calcium or
phosphate
increased blood
levels of calcium,
uric acid, potassium,
bilirubin, blood
sugars, or c-reactive
protein
liver problems
including an
increase in your liver
enzymes in the
blood
blood clot in the
lungs
nose bleed
change in voice;
hoarseness
pain in throat
wheezing
pulmonary
hypertension
possible fluid in the
lung
rash
itchy or redness of
skin
increase sweating
runny nose or nasal
congestion
urinary tract
infection
inflammation of the
nose and throat
flu-like symptoms
(influenza)
lung infection
serious infection in
the blood
viral infection
flushing
infection and/or
irritation of the
stomach and bowels
feeling unwell
blurred vision
cataract
infusion reactions
such as pain,
swelling, irritation or
discomfort at site of
injection
low blood pressure
blood clots in veins
dehydration
bone and muscle
pain,
muscle weakness
aching muscles
kidney problems,
decreased ability to
make urine and
failure
abnormal sensation
(tingling) or
decreased sensation
in arms and legs
anxiety
Uncommon (may affect up to 1 in 100 patients)
sudden loss of heart
function
build-up of fluid
around the heart
bleeding, itchy skin,
yellow skin, very
pale stools caused
by blocking of bile
bleeding in the
stomach and bowels
multi-organ failure
allergic reaction to
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severe increase in
blood pressure
stroke
decreased blood
supply to the heart
bleeding around the
brain
bleeding in the lungs
flow from the liver
liver failure
severe infection of
the blood causing
low blood pressure
and low blood flow
to organs. lung
problems
re-infection of the
liver with hepatitis B
virus
carfilzomib
breakdown products
of the cancer cells
entering the blood
stream (Tumor Lysis
Syndrome)
Thrombotic
thrombocytopenic
purpura (TTP)
Blockage of the
intestines
Inflammation of the
pancreas gland
Posterior reversible
encephalopathy
syndrome (PRES)
Rarely (may affect up to 1 in 1000 people)
Hemolytic uremic syndrome (HUS)
Thrombotic microangiopathy
Swelling and irritation of the lining around the heart
Swelling of the throat
Hole in the stomach, small intestines or large bowel
Infection of the back of the eye (cytomegalovirus)
The following side effects have been seen in people who received carfilzomib. It is
unknown if they were caused by carfilzomib, you may or may not experience these
side effects:
Tiredness, infection, and easy bruising or bleeding which may be symptoms
of a blood condition known as Myelodysplastic syndrome/Acute Myeloid
Leukemia (MDS/AML).
Tenderness of pain in the abdomen that gets more intense with motion or
touch, abdominal bloating or distention, nausea and vomiting, diarrhea,
constipation or the inability to pass gas which may be symptoms of swelling of
the thin tissue that lines the inner wall of the abdomen and covers most of the
abdominal organs
Blurred or double vision, vision loss, difficulty speaking, weakness in an arm
or a leg, a change in the way you walk, problems with your balance,
persistent nmbness, decreased sensation or loss of sensation, decreased
alertness, memory loss or confusion which may be symptoms of a central
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nervous 
system 
infection 
known 
as 
Progressive 
Multifuocal
Leukoencephalopathy (PML).
Driving and Using Machines
You may experience fatigue, dizziness, fainting, and/or a drop in blood pressure after
treatment with carfilzomib. This may impair your ability to drive or operate machinery.
If you have these symptoms, you should not drive a car or operate machinery.
Hydration Risks
There may be risks associated with over hydrating (having too much fluid in your
body) so it is important to follow your doctor's instructions regarding how much water
or other fluids you should drink. Over hydration can cause side effect to your heart,
lungs, and kidneys.
Other Risks
Blood draws
Blood draws may cause pain, bleeding , and/or bruising. You may fa int and/or
develop an infection with redness and irritation of the vein at the site where blood is
drawn. Frequent blood collection may cause anemia (low red blood cell count), which
may create a need for blood transfusions.
Bone marrow aspirations/biopsies
Bone marrow biopsies and aspirations may cause pain, bruising, bleeding, redness,
low blood pressure, swelling, and/or infection at the site of the aspiration/biopsies. An
allergic reaction to the anesthetic may occur. A scar may form at the
aspiration/biopsy site.
CT Scans
CT scans involve exposure to radiation. Although the amount of radiation exposure is
higher than a typical x-ray, the risk of harmful effects from a single exam is very
small. The dye that is injected into a vein for the scan is usually well tolerated. Some
people feel dizzy or queasy or get a headache with it or notice a cold feeling near the
injection site. There is a chance of having an allergic reaction to the dye that rarely
can be serious and life threatening. Your radiologist will obtain a separate informed
consent explaining this procedure in specific detail.
Questionnaires
Questionnaires may contain questions that are sensitive in nature. You may refuse to
answer any question that makes you feel uncomfortable. If you have concerns after
completing the questionnaire, you are encouraged to contact your doctor or the study
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chair.
It is possible that other rare side effects could occur which are not described in this
consent form. It is also possible that you could have a side effect that has not
occurred before.
Pregnancy Risks
It is possible that the medicines used in this study could injure a fetus if you, or your
partner, becomes pregnant while taking them. You have already been told what is
known about this possibility, and you are encouraged to ask further questions.
You may want to discuss this with others before you agree to take part in this study.
If you wish, we will arrange for a doctor, nurse, or counselor who is not part of this
study to discuss the potential risks and benefits with you and anyone else you want
to have present.
Because of the potential risks, you, or your partner, must not become pregnant while
you are participating in this study. Women must have a negative pregnancy test
within 10-14 days and 24 hours before entering the study.
* For the purposes of this study, a female of childbearing potential is a sexually
mature female who: 1) has not undergone a hysterectomy (the surgical removal of
the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
has had menses at any time during the preceding 24 consecutive months).
If you have regular or no menstrual cycles, you will then have pregnancy tests every
week for the first 28 days, then every 28 days while taking cabozantinib, again when
taken off of cabozantinib therapy and 28 days after having stopped taking
cabozantinib. If you have irregular menstrual cycles, you will have pregnancy tests
every week for the first 28 days, then every 14 days while taking cabozantinib.
If you are sexually active and can get pregnant, or can get your partner pregnant, you
must use TWO appropriate method(s) of birth control every time you have sex, or you
must not have sex. Both male and females must agree to use a medically accepted
barrier method of birth control (contraception) plus one additional highly effective
method of birth control (contraception) at the SAME TIME.
Highly Effective Methods:
Intrauterine device (IUD) or intrauterine system [IUS])
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Additional Effective Methods
Tubal ligation
Male vasectomy
If an IUD method is not medically possible for you, you may use another highly
effective method or two barrier methods AT THE SAME TIME.
These birth control methods must be used during the following time periods related to
this study:
1) for at least 28 days before starting cabozantinib therapy;
2) while participating in the study; during interruptions in therapy and
3) for at least 4 months after cabozantinib has been stopped
Because of the nature of this research, methods of natural family planning are not, by
themselves, sufficiently reliable to avoid pregnancy.
Special Note: Certain HIV-protease inhibitors, griseofulvin, modafinil, pencillins ,
rifampin, rifabutin , phenytoin, carbamazepine, or certain herbal supplements such as
St. John's Wort may reduce the effectiveness of hormonal contraceptives during and
up to one month after discontinuation of these concomitant therapies. Therefore,
females of childbearing potential requiring treatment with one or more of these drugs
must choose ONE non-hormonal method as the highly effective method of birth
control (IUD, tubal ligation, partner's vasectomy) along with ONE of the additional
effective methods (latex condom, diaphragm, cervical cap) or abstain from
heterosexual contact while taking cabozantinib.
FOR ALL MALES
You must NEVER have unprotected sexual contact with a female who can become
pregnant. Because it is not known whether cabozantinib is present in semen, you
must completely abstain from sexual contact with females who are pregnant or able
to become pregnant, or use a latex condom every time you engage in any sexual
contact with females who are pregnant or may become pregnant. You must do this
while taking cabozantinib and for 28 days after you stop taking cabozantinib, even if
you have had a successful vasectomy.
You can get additional information about methods to avoid pregnancy by calling the
UNMC Research Subject Advocate's Office at (402) 559-6941.
You will need to continue to avoid pregnancy for 4 months after finishing the
research.
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By signing this and being in the study, you are agreeing to not get pregnant while you
are on the study and for 4 months after. Should you become pregnant while on this
study, you should immediately notify the study personnel. The investigator will assist
you in finding appropriate medical care. The investigator also may ask to be allowed
to continue getting information about your pregnancy. You can refuse to provide this
information.
What are the possible benefits to you?
Phase I of the study will be looking for the highest dose of cabozantinib that can be
given safely. You may not get any benefit from being in this research study.
What are the possible benefits to other people?
Future patients may benefit from what is learned. Specifically, in the current study,
we aim to treat the patients with MM who progressed on carfilzomib. It is hoped that
by treating patients with cabozantinib, this may improve response to the carfilzomib
therapy that has proven to result in improved outcomes in MM patients.
What are the alternatives to being in this research study?
You may choose not to take part in this study. You may choose to receive standard
of-care therapy for the disease The standard-of-care options that are available to you
will be based on what therapies you may have already had. The study doctor and
your regular doctor will discuss the options with you in more detail. You may choose
to receive other investigational therapy, if available. You may choose not to have
treatment for cancer at all. In all cases, you will receive appropriate medical care,
including treatment for pain and other symptoms of cancer.
What will being in this research study cost you?
The investigational drug, cabozantinib is provided by the manufacturer, Exelixis, at no
cost to you for the entire time you are on the study. Some tests and procedures that
you may receive as part of this study and are for research purposes only will be
without cost to you. Standard medical care that you receive under this research study
will be billed to your insurance provider and/or you in the ordinary manner.
However, your insurance provider and/or you may be financially responsible for the
cost of care and treatment of any complications resulting from the research tests,
procedures, and/or drugs, including hospitalization, nausea, vomiting, low blood cell
counts, and dehydration.
You will be responsible for any applicable insurance deductibles and co-payments. If
you wish to speak with a financial counselor about your insurance coverage and
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benefits, let the investigator or other study personnel know. A contact for personal
assistance will be made available for you.
Will you be paid for being in this research study?
You will not be paid to be in this research study.
Who is paying for this research?
This research is being paid for by grant funds from Amgen. The Institution receives
money from Amgen and study drug from Exelixis to conduct this study.
Dr. Muhamed Baljevic, the Principal Investigator of this study, receives money as an
independent consultant for participating on an Advisory Board for Amgen, Inc..
What should you do if you are injured or have a medical problem during this
research study?
Your welfare is the main concern of every member of the research team. If you are
injured or have a medical problem as a direct result of being in this study, you should
immediately contact one of the people listed at the end of this consent form.
Emergency medical treatment for this injury or problem will be available at the
Nebraska Medical Center. If there is not sufficient time, you should seek care from a
local health care provider.
The Institution has no plans to pay for any required treatment or provide other
compensation. If you have insurance, your insurance company may or may not pay
the costs of medical treatment. If you do not have insurance, or if your insurance
company refuses to pay, you will be expected to pay for the medical treatment.
Agreeing to this does not mean you have given up any of your legal rights.
How will information about you be protected?
You have rights regarding the protection and privacy of your medical information
collected before and during this research. This medical information is called
"protected health information" (PHI). PHI used in this study may include your medical
record number, address, birth date, medical history, the results of physical exams,
blood tests, x-rays as well as the results of other diagnostic medical or research
procedures. Only the minimum amount of PHI will be collected for this research. Your
research and medical records will be maintained in a secure manner.
Who will have access to information about you?
By signing this consent form, you are allowing the research team to have access to
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your PHI. The research team includes the investigators listed on this consent form
and other personnel involved in this specific study at the Institution.
Your PHI will be used only for the purpose(s) described in the section "What is the
reason for doing this research study?"
You are also allowing the research team to share your PHI, as necessary, with other
people or groups listed below:
The UNMC Institutional Review Board (IRB)
Institutional officials designated by the UNMC IRB
Federal law requires that your information may be shared with these groups:
The HHS Office of Human Research Protections (OHRP)
The Food and Drug Administration (FDA)
The HIPAA Privacy Rule requires the following groups to protect your PHI:
Researchers at MD Anderson.
Your health insurance company
The Fred and Pamela Buffett Cancer Center Scientific Review
Committee (SRC)
Your PHI may also be shared with the following groups. However, these
organization(s) do not have the same obligation to protect your PHI:
Exelixis Corporation, the manufacturer of cabozantinib and Amgen, which
provides funds the Institution to conduct this research
The National Cancer Institute's (NCI) Clinical Trial Reporting Program
There is currently no plan to end this study. Your information may be kept and used
indefinitely.
You may cancel your authorization for further collection of PHI for use in this
research at any time by contacting the principal investigator in writing. However, the
PHI which is included in the research data obtained to date may still be used. If you
cancel this authorization, you will no longer be able to participate in this research.
How will results of the research be made available to you during and after the
study is finished?
In most cases, the results of the research can be made available to you when the
study is completed, and all the results are analyzed by the investigator or the sponsor
of the research. The information from this study may be published in scientific
journals or presented at scientific meetings, but your identity will be kept strictly
confidential.
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If you want the results of the study, contact the Principal Investigator at the phone
number given at the end of this form or by writing to the Principal Investigator at the
following address:Dr. Muhamed Baljevic, 986840 Nebraska Medical Center, Omaha,
NE 68198-6840
A description of this clinical trial will be available on www.ClinicalTrials.gov, as
required by U.S. law. This website will not include information that can identify you. At
most, the website will include a summary of the results. You can search this website
at any time.
What will happen if you decide not to be in this research study?
You can decide not to be in this research study. Deciding not to be in this research
will not affect your medical care or your relationship with the investigator or the
Institution. Your doctor will still take care of you and you will not lose any benefits to
which you are entitled.
What will happen if you decide to stop participating once you start?
You can stop participating in this research (withdraw) at any time by contacting the
Principal Investigator or any of the research staff.
Deciding to withdraw will otherwise not affect your care or your relationship with the
investigator or this institution. You will not lose any benefits to which you are entitled.
For your safety, please talk to the research team before you stop taking any study
drugs or stop other related procedures. They will advise you how to withdraw safely.
If you withdraw you may be asked to undergo some additional tests. You do NOT
have to agree to do these tests.
You may be taken off the study if you do not follow instructions of the investigator or
the research team.
You may also be taken off the study if
your disease progresses after two cycles
you have unacceptable side effects from the study treatment
the investigator determines that you condition has changed and that the study
treatment is unacceptable
you are unable to continue to have the ability to provide consent for yourself
your response to treatment qualifies you for another therapy, such as high
dose therapy with autologus stem cell transplant.
Any research data obtained to date may still be used in the research.
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Will you be given any important information during the study?
You will be informed promptly if the research team gets any new information during
this research study that may affect whether you would want to continue being in the
study.
What should you do if you have any questions about the study?
You have been given a copy of "What Do I Need to Know Before Being in a
Research Study?" If you have any questions at any time about this study, you should
contact the Principal Investigator or any of the study personnel listed on this consent
form or any other documents that you have been given.
What are your rights as a research participant?
You have rights as a research subject. These rights have been explained in this
consent form and in The Rights of Research Subjects that you have been given. If
you have any questions concerning your rights, or want to discuss problems,
concerns, obtain information or offer input, or make a complaint about the research,
you can contact any of the following:
The investigator or other study personnel
Institutional Review Board (IRB)
Telephone: (402) 559-6463.
Email: IRBORA@unmc.edu
Mail: UNMC Institutional Review Board, 987830 Nebraska Medical
Center, Omaha, NE 68198-7830
Research Subject Advocate
Telephone: (402) 559-6941
Email: unmcrsa@unmc.edu
Optional Storage of Your Samples
The researchers doing this study are interested in doing research now on the blood
and bone marrow aspirate samples collected from you to better understand the
nature of cancer and how patients respond to treatment. Rapid advances in
technology make it impossible to predict what new tests or studies may be possible in
the future.
The collection of these research samples will be before you begin treatment and
before cycle 3 are a necessary part of this study and will be used only for these
purposes. The samples will not be sold.
However, with your permission should these research samples not be used for this
study then we would like to ask you if you will allow them to be saved and stored for
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future use. The samples will be kept until they are used up or destroyed.
Most future research studies will focus on cancer, specifically multiple myeloma. This
may also include research on inherited traits also known as hereditary genetic testing
(to find out if cancer runs in your family).
Reports about any research tests done with your samples will not be given to you or
your oncologist, or family doctor. These reports will not be put in your medical
records.
Confidentiality of Samples
To protect your identity, the information that will be on your research blood and tissue
samples will be limited to your pathology identification number and participant code,
which may include your initials.
To protect your identity, the information that will be on your blood samples will be
limited to the participant code, which may include your initials.
Withdrawal of Required Samples
If you agree to allow the investigators to store your research samples and then
decide you no longer want your samples to be used for future research, you should
tell the investigator. The investigator will ensure the samples stored are destroyed. If
tests have already been done on your sample(s) it will not be possible to withdraw
those results. However, no further testing will be done.
This research may not benefit you, but may help people in the future who have the
same kind of cancer as you have. You can indicate your wish to participate in this
additional research, and have your samples stored for future research purposes
when signing this consent form. You may decide not to participate in the "optional"
study and still participate in this main study.
_____ You agree to allow storage and use of bone marrow aspirate and blood
samples taken from you for future research.
_____ You do not agree to storage and use of bone marrow aspirate and blood
samples to be stored for future research.
Documentation of informed consent
You are freely making a decision whether to be in this research study. Signing this
form means that:
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You have read and understood this consent form.
You have had the consent form explained to you.
You have been given a copy of The Rights of Research Subjects
You have had your questions answered.
You have decided to be in the research study.
If you have any questions during the study, you have been directed to talk to
one of the investigators listed below on this consent form.
You will be given a signed and dated copy of this consent form to keep.
Printed Name of Subject ___________________________
Signature of Subject ___________________________
Date ___________
My signature certifies that all the elements of informed consent described on this
consent form have been explained fully to the subject. In my judgment, the subject
possesses the legal capacity to give informed consent to participate in this research
and is voluntarily and knowingly giving informed consent to participate.
Printed Name of Person obtaining consent ___________________________
Signature of Person obtaining consent ___________________________
Date ___________
Authorized Study Personnel
Principal
* Baljevic, Muhamed
phone: 402-559-8562
alt #: 402-559-8013
degree: MD
 
 
Secondary
* Holstein, Sarah
phone: 402-559-6660
alt #: 402-559-8013
degree: MD
 
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Institutional Review Board (IRB)
What Do I Need To Know
Before Being In A Research Study?
You have been invited to be in a research study. Research studies are also called
"clinical trials" or "protocols." Research is an organized plan designed to get new
knowledge about a disease or the normal function of the body. The people who are in
the research are called research subjects. The investigator is the person who is
running the research study. You will get information from the investigator and the
research team, and then you will be asked to give your consent to be in the
research.
This sheet will help you think of questions to ask the investigator or his/her
staff. You should know all these answers before you decide about being in the
research.
What is the purpose of the research? Why is the investigator doing the research?
What are the risks of the research? What bad things could happen?
What are the possible benefits of the research? How might this help me?
How is this research different than the care or treatment I would get if I wasnˆt in
the research? Are there other treatments I could get?
Does everyone in this research study get the same treatment?
Will being in the research cost me anything extra?
Do I have to be in this research study? Will the doctor still take care of me if I say no?
Can I stop being in the research once Iˆve started? How?
Who will look at my records?
How do I reach the investigator if I have more questions?
Who do I call if I have questions about being a research subject?
Make sure all your questions are answered before you decide whether or not to
be in this research.
Academic Research & Services Building 3000  /  987830 Nebraska Medical Center  /  Omaha NE  68198-7830
402-559-6463  /  FAX 402-559-3300 / Email: irbora@unmc.edu  /   http://www.unmc.edu/irb


Institutional Review Board (IRB)
THE RIGHTS OF RESEARCH SUBJECTS
AS A RESEARCH SUBJECT YOU HAVE THE RIGHT ˆ
ˆ to be told everything you need to know about the research before you are
asked to decide whether or not to take part in the research study. The research
will be explained to you in a way that assures you understand enough to decide
whether or not to take part.
ˆ to freely decide whether or not to take part in the research.
ˆ to decide not to be in the research, or to stop participating in the research at
any time. This will not affect your medical care or your relationship with the
investigator or the Nebraska Medical Center. Your doctor will still take care of you.
ˆ to ask questions about the research at any time. The investigator will answer
your questions honestly and completely.
ˆ to know that your safety and welfare will always come first. The investigator will
display the highest possible degree of skill and care throughout this research. Any
risks or discomforts will be minimized as much as possible.
ˆ to privacy and confidentiality. The investigator will treat information about you
carefully, and will respect your privacy.
... to keep all the legal rights you have now. You are not giving up any of your
legal rights by taking part in this research study.
ˆ to be treated with dignity and respect at all times
The Institutional Review Board is responsible for assuring that your rights and
welfare are protected. If you have any questions about your rights, contact the
Institutional Review Board at (402) 559-6463.
Academic Research & Services Building 3000  /  987830 Nebraska Medical Center  /  Omaha NE  68198-7830
402-559-6463  /  FAX 402-559-3300 / Email: irbora@unmc.edu  /   http://www.unmc.edu/irb
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