7. study calendar and assessments
6.3 response durability

| 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                                                     | X                                                   | X                                                            | X  | X      |    |    |                         |    |    |
| examination 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            | X                                                   | X4                                                           | X  | X      | X  | X  |                         |    |    |
| phosphatase, lactate dehydrogenase, uric acid 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      |    |    |                         |    |    |  
UNMC IRB \#434-17 Protocol Version 5.4 Dated 04-20-21 Page 58 of 105 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
7. study calendar and assessments
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.
7. study calendar and assessments
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)cyclopropane1,1-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.  
| 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. 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).
7. study calendar and assessments
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)
- 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 8.2.2 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.
7. study calendar and assessments
very common (may affect more

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.  
| - swelling of hands, feet or  ankles - headache - high blood pressure - pain - musclespasms - 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)   |
|-----------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|
7. study calendar and assessments
common (may affect up to

| - 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 creactive protein           | - low blood pressure - blood clots in veins - bone and muscle pain muscle weakness - kidney problems,  decreasing ability to make  urine and failure - anxiety |  
| - 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 - bleeding around the  to the heart 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  - liverfailure - bleeding in the lungs •increased blood pressure inthe lungs (possibledifficulty 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
7. study calendar and assessments
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.
7. study calendar and assessments
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 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.
7. study calendar and assessments
9. toxicity and adverse event

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).
7. study calendar and assessments
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.
7. study calendar and assessments
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.
7. study calendar and assessments
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.
7. study calendar and assessments
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.
7. study calendar and assessments
9.1 adverse event reporting and

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-  
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.
7. study calendar and assessments
9.1.2 fred & pamela buffett

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. 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
7. study calendar and assessments
9.1.3 food and drug administration

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.  
  
  
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.
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.
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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:
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.
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10. statistical considerations 10.1 study

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;
(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.
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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.
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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 Patient achieves a level of response that qualifies him or her for another therapy, such as high dose therapy with autologous stem cell transplantation.
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10.5 analysis of gene expression

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.
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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.
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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.
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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-tophenotype 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.
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10.6 analysis of symptom burden

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 QLQMY20 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.
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10.7 reporting and exclusions 10.7.1

All patients will be evaluable for toxicity from the time of their first treatment with cabozantinib.
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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.
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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).
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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.). - 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.
7. study calendar and assessments
11.2 forte electronic data capturing

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

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.
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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.
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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)
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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.
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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.
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12.7 subject/representative comprehension when the

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.
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12.8 information purposely withheld.

The results of the tests done solely for research purposes will not be disclosed to the subject. No other information will be purposely withheld from the subject.
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12.9 potential benefits of the

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.
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12.10potential 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.
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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.
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12.12therapeutic 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.
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12.13risk/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.
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12.14consent form documents

The consent document used in this study will include the adult consent document.
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13. references

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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 microarraybased 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 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.  
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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.  
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14.0 data collection forms
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                                                                                                                                                                                                                                                                          | Institution:   | Subject ID:                   | Checklist #:   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-------------------------------|----------------|
| Completed:                                                                                                                                                                                                                                                                    | Investigator:  | 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: | Yes            | No N/A                        |                |
| [ ]                                                                                                                                                                                                                                                                           | [              | ] 1.                          |                |  
Date Completed:
Institution:
Investigator:
Subject ID: Checklist #:
Protocol v5.2 dated 08-23-19 Inclusion Criteria:  
  
  
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,
[ ] [ ] 2. [ ] [ ] 3.  
[ ] [ ] 4.  
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:
[ ] [ ] 5. [ ] [ ] 6.  
[ ] [ ] 7.  
[ ] [ ] 8. [ ] [ ] 9.  
_____ 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  of the initiation of treatment bone marrow plasmacytosis of ≥50%  
 following:
values
[ ] [ ] 10.  
 following:
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.  
  
Absence of myocardial infarction in the previous 6 months
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.  
| 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.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|-----------------------------|---------|
| 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 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.                                                                                                                                                                                                                                                                                                                               | [ ]                                                                      | [                           | ]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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | [ ]                                                                      | [                           | ]2.     |
| 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | [ ]                                                                      | [                           | ]3.     |
| 4. Patients with a known history of allergic reactions attributed to compounds of similar  chemical or biologic composition to cabozantinib.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | [ ]                                                                      | [                           | ]4.     |
| 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. | [ ]                                                                      | [                           | ]5.     |
| 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | [ ]                                                                      | [                           | ]6.     |  
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.  
[ ] [ ]7.  
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.  
[ ] [ ]12.  
[ ] [ ] 13.  
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
[ ] [ ]8.  
[ ] [ ]9.  
[ ] [ ]10. [ ] [ ]11.  
[ ] [ ] 14.  
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).  
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;  
| 15. The subject has radiographic evidence of cavitating pulmonary lesion(s); 16. The subject has tumor invading or encasing any major blood vessels;   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|  
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. Eligibility: [ ] Patient satisfies all criteria.   [ ] Patient not formally eligible, but admitted to study because (state reason);   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
[ ] [ ] 15. [ ] [ ] 16.  
[ ] [ ] 17. [ ] [ ] 18.  
[ ] [ ] 19. [ ] [ ] 20. [ ] [ ] 21.  
[ ] [ ] 22.
14.0 data collection forms
appendix b mdasi - mm

Part I. How severe are your symptoms?  
People with cancer frequently have symptoms that are caused by their disease or by their treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. Please fill in the circle  
| below from 0 (symptom has not been present) to 10 (the symptom was as bad as you can imagine it could   |                                     |    |    |    |    |    |    |    |    |    |    |    |
|---------------------------------------------------------------------------------------------------------|-------------------------------------|----|----|----|----|----|----|----|----|----|----|----|
| be) for each item.                                                                                      | As Bad As You                       |    |    |    |    |    |    |    |    |    |    |    |
| Not                                                                                                     |                                     |    |    |    |    |    |    |    |    |    |    |    |
| Present                                                                                                 | Can Imagine                         |    |    |    |    |    |    |    |    |    |    |    |
| 0                                                                                                       | 1                                   | 2  | 3  | 4  | 5  | 6  | 7  | 8  | 9  | 10 |    |    |
| o                                                                                                       | o                                   | o  | o  | o  | o  | o  | o  | o  | o  | o  |    |    |
| 1.                                                                                                      | Your pain at its WORST?             |    |    |    |    |    |    |    |    |    |    |    |
| 2.                                                                                                      | Your fatigue (tiredness) at         | o  | o  | o  | o  | o  | o  | o  | o  | o  | o  | o  |
| its WORST?                                                                                              | o                                   | o  | o  | O  | o  | O  | o  | o  | O  | o  | o  |    |
| 3.                                                                                                      | Your nausea at its WORST?           |    |    |    |    |    |    |    |    |    |    |    |
| Your disturbed sleep at its                                                                             |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 4.                                                                                                      | o                                   | o  | o  | o  | o  | o  | o  | o  | o  | o  | o  |    |
| WORST?                                                                                                  |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 5.                                                                                                      | Your feelings of being distressed   | o  | O  | O  | o  | o  | O  | O  | O  | O  | o  | O  |
| (upset) at its WORST?                                                                                   |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 6.                                                                                                      | Your shortness of breath at its     | O  | o  | O  | o  | o  | o  | o  | O  | o  | o  | o  |
| WORST?                                                                                                  |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 7.                                                                                                      | Your problem with remembering       | O  | o  | o  | o  | o  | o  | o  | o  | o  | o  |    |
| o                                                                                                       |                                     |    |    |    |    |    |    |    |    |    |    |    |
| things at its WORST?                                                                                    |                                     |    |    |    |    |    |    |    |    |    |    |    |
| Your problem with lack of appetite                                                                      |                                     |    |    |    |    |    |    |    |    |    |    |    |
| a.                                                                                                      | o                                   | o  | O  | o  | o  | o  | o  | o  | o  | o  | o  |    |
| at its WORST?                                                                                           |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 9.                                                                                                      | Your feeling drowsy (sleepy) at its | O  | o  | o  | o  | o  | o  | o  | O  | o  | o  | o  |
| WORST?                                                                                                  |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 10. Your having a dry mouth at its                                                                      | o                                   | o  | O  | o  | o  | o  | o  | o  | o  | o  | o  |    |
| WORST?                                                                                                  |                                     |    |    |    |    |    |    |    |    |    |    |    |
| 1. Your feeling sad at its WORST?                                                                       | O                                   | O  | O  | o  | o  | o  | o  | o  | O  | o  | O  |    |
| 12. Your vomiting at its WORST?                                                                         | o                                   | o  | O  | o  | o  | o  | o  | o  | o  | o  | o  |    |
| 13. Your numbness or tingling at                                                                        | o                                   | o  |    |    |    |    |    |    |    |    |    |    |
| its WORST?                                                                                              | o                                   | o  | o  | o  | o  | o  | o  | o  | o  |    |    |    |
| Copyright 1999 The University of Texas M. D. Anderson Cancer Center                                     |                                     |    |    |    |    |    |    |    |    |    |    |    |
| Page 1 of 2                                                                                             | All rights reserved.                |    |    |    |    |    |    |    |    |    |    |    |  
| Not                                     | As Bad As You   |             |    |    |    |    |    |    |    |    |    |
|-----------------------------------------|-----------------|-------------|----|----|----|----|----|----|----|----|----|
| M                                       | Present         | Can Imagine |    |    |    |    |    |    |    |    |    |
| 2                                       | 3               | 4           | 5  | 6  | 7  | 8  | 9  |    |    |    |    |
| 0                                       | 10              |             |    |    |    |    |    |    |    |    |    |
| 14. Your constipation at its WORST?   O | o               | o           | o  | o  | o  | O  | o  | o  | o  | o  |    |
| 15. Your muscle weakness at its         | o               | O           | o  | O  | O  | O  | O  | o  | O  | o  | o  |
| WORST?                                  |                 |             |    |    |    |    |    |    |    |    |    |
| 16. Your diarrhea (loose stools) at its | o               | o           | O  | o  | o  | O  | o  | o  | o  | o  |    |
| WORST?                                  |                 |             |    |    |    |    |    |    |    |    |    |
| 17. Your sore mouth or throat at its    | o               | o           | o  | o  | o  | o  | o  | o  | o  | o  | o  |
| WORST?                                  |                 |             |    |    |    |    |    |    |    |    |    |
| 18. Your rash at its WORST?             | o               | o           | o  | o  | o  | o  | o  | o  | O  | O  | o  |
| 19. Your problem with Paying            | o               | o           | o  |    |    |    |    |    |    |    |    |
| Attention (Concentrating) at its        | o               | o           | o  | O  | O  | O  | O  | O  |    |    |    |
| WORST?                                  |                 |             |    |    |    |    |    |    |    |    |    |
| 20. Your bone aches at its WORST?       | o               | o           | O  | o  | o  | o  | o  | o  | o  | o  | o  |  
Part II. How have your symptoms interfered with your life?  
Symptoms frequently interfere with how we feel and function. How much have your symptoms interfered with the  
| following items in the last 24 hours:                               | Did Not              | Interfered   |    |    |    |    |    |     |    |    |    |
|---------------------------------------------------------------------|----------------------|--------------|----|----|----|----|----|-----|----|----|----|
| Interfere                                                           | Completely           |              |    |    |    |    |    |     |    |    |    |
| 2                                                                   | 3                    | 4            | 5  | 6  | 7  | 8  | 9  | 110 |    |    |    |
| 0                                                                   | 1                    |              |    |    |    |    |    |     |    |    |    |
| 21. General activity?                                               | o                    | o            | o  | O  | o  | o  | o  | o   | o  | O  | o  |
| 2. Mood?                                                            | o                    | o            | o  | O  | O  | O  | o  | o   | o  | o  | O  |
| 2.  Work (including work around                                     | o                    | o            | o  | o  | o  | o  | o  | o   | o  | o  | O  |
| the house)?                                                         |                      |              |    |    |    |    |    |     |    |    |    |
| 2. Relations with other people?                                     | o                    | o            | o  | o  | o  |    |    |     |    |    |    |
| o                                                                   | o                    | o            | o  | o  | o  |    |    |     |    |    |    |
| o                                                                   | o                    | o            | o  | o  | o  | O  | o  | o   | o  | o  |    |
| 25. Walking?                                                        |                      |              |    |    |    |    |    |     |    |    |    |
| 26. Enjoyment of life?                                              | O                    | O            | O  | O  | O  | O  | o  | o   | o  | o  | o  |
| Copyright 1999 The University of Texas M. D. Anderson Cancer Center |                      |              |    |    |    |    |    |     |    |    |    |
| Page 2 of 2                                                         | All rights reserved. |              |    |    |    |    |    |     |    |    |    |
14.0 data collection forms
eortc qlq-c30 (version 3)

We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will  
| remain strictly confidential.                    |                                                                       |        |       |       |      |
|--------------------------------------------------|-----------------------------------------------------------------------|--------|-------|-------|------|
| Please fill in your initials:                    | iiii                                                                  |        |       |       |      |
| Your birthdate (Day, Month, Year):               | i                                                                     |        |       |       |      |
| Today's date (Day, Month, Year):                 | 31 LUTUUT                                                             | Not at | A     | Quite | Very |
| AII                                              | Little                                                                | a Bit  | Much  |       |      |
| 1.1.                                             | Do you have any trouble doing strenuous activities,                   |        |       |       |      |
| like canying a heavy shopping bag or a suitcase? | l                                                                     | 2      | 3     | 4     |      |
| 2.                                               | Do you have any trouble taking a long walk?                           | l      | 2     | 3     | 4    |
| 3.                                               | Do you have any trouble taking a short walk outside of the house?     | l      | 2     | 3     | 4    |
| 4.                                               | Do you need to stay in bed or a chair during the day?                 | l      | 2     | 3     | 4    |
| 5.                                               | Do you need help with eating, dressing, washing                       |        |       |       |      |
| yourself or using the toilet?                    | l                                                                     | 2      | 3     | 4     |      |
| During the past week:                            | Not at                                                                | A      | Quite | Very  |      |
| AII                                              | Little                                                                | a Bit  | Much  |       |      |
| 6.                                               | Were you limited in doing either your work or other daily activities? | l      | 2     | 3     | 4    |
| 7.                                               | Were you limited in pursuing your hobbies or other                    | l      | 2     | 3     | 4    |
| leisure time activities?                         |                                                                       |        |       |       |      |
| 8.                                               | Were you short of breath?                                             | i      | 2     | 3     | 4    |
| 9.                                               | Have you had pain?                                                    | l      | 2     | 3     | 4    |
| 10. Did you need to rest?                        | l                                                                     | 2      | 4     |       |      |
| 3                                                |                                                                       |        |       |       |      |
| 1. Have you had trouble sleeping?                | i                                                                     | 2      | 3     | 4     |      |
| 12. Have you felt weak?                          | l                                                                     | 2      | 3     | 4     |      |
| 13. Have you lacked appetite?                    | l                                                                     | 2      | 3     | 4     |      |
| 14. Have you felt nauseated?                     | l                                                                     | 2      | 3     | 4     |      |
| 15. Have you vomited?                            | 1                                                                     | 2      | 3     | 4     |      |
| 16. Have you been constipated?                   | 2                                                                     |        |       |       |      |
| l                                                | 3                                                                     | 4      |       |       |      |
| Please go on to the next page                    |                                                                       |        |       |       |      |  
ENGLISH
During the past week:  
  
| 17. Have you had diarrhea?   |
|------------------------------|  
| 18. Were you tired?   |
|-----------------------|  
| 19. Did pain interfere with your daily activities?   |
|------------------------------------------------------|  
20. Have you had difficulty in concentrating on things, like reading a newspaper or watching television?  
21. Did you feel tense?  
2. Did you wony?  
23. Did you feel initable? 24. Did you feel depressed?  
| 25. Have you had difficulty remembering things?   |
|---------------------------------------------------|  
| 26. Has your physical condition or medical treatment   |
|--------------------------------------------------------|
| interfered with your family life?                      |  
27. Has your physical condition or medical treatment interfered with your social activities?  
2. Has your physical condition or medical treatment caused you financial difficulties?  
For the following questions please circle the number between 1 and 7 that best applies to you  
  
  
APPENDIX D: EORTC QLQ-MY20 TOOL
A
14.0 data collection forms
eortc qlq - my20

Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you have experienced these symptoms or problems during the past week. Please answer by circling the number that best applies to you.  
| During the past week:                    | Not at                                          | A     | Quite   |    |
|------------------------------------------|-------------------------------------------------|-------|---------|----|
| All                                      | Little                                          | a Bit |         |    |
| 31. Have you had bone aches or pain?     | i                                               | 2     | 3       |    |
| Have you had pain in your back?          | 2                                               |       |         |    |
| 32.                                      | 1                                               | 3     |         |    |
| 3.                                       | Have you had pain in your hip?                  | 1     | 2       | 3  |
| 34.                                      | Have you had pain in your arm or shoulder?      | l     | 2       | 3  |
| 35.                                      | Have you had pain in your chest?                | i     | 2       | 3  |
| 36.                                      | If you had pain did it increase with activity?  | 1     | 2       | 3  |
| 37.                                      | Did you feel drowsy?                            | 1     | 2       | 3  |
| 38.                                      | Did you feel thirsty?                           | l     | 2       | 3  |
| 39.                                      | Have you felt ill?                              | I     | 2       | 3  |
| 40.                                      | Have you had a dry mouth?                       | 1     | 2       | 3  |
| 41.                                      | Have you lost any hair?                         | 1     | 2       | 3  |
| 42.                                      | Answer this question only if you lost any hair: |       |         |    |
| Were you upset by the loss of your hair? | l                                               | 2     | 3       |    |
| 43.                                      | Did you have tingling hands or feet?            | 1     | 2       | 3  |
| 4.                                       | Did you feel restless or agitated?              | l     | 2       | 3  |
| 45.                                      | Have you had acid indigestion or heartburn?     | i     | 2       | s  |
| 46. Have you had burning or sore eyes?   | l                                               | 2     | 3       |    |  
| Very   |
|--------|
| Much   |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |
| 4      |  
Please turn to next page  
| ENGLISH                                                  |              |       |      |    |
|----------------------------------------------------------|--------------|-------|------|----|
| During the past week:                                    | Not at       | Quite | Very |    |
| A                                                        |              |       |      |    |
| All                                                      | Little a Bit | Much  |      |    |
| 47. Have you felt physically less attractive as a result |              |       |      |    |
| of your disease or treatment?                            | l            | 2     | 3    | 4  |
| 48. Have you been thinking about your illness?           | l            | 2     | 3    | 4  |
| 49. Have you been worried about dying?                   | l            | 2     | 3    | 4  |
| 50. Have you worried about your health in the future?    | l            | 2     | s    | 4  |
appendix e ecog performance status
eortc qlq - my20

| ECOG Performance Status Scale                                                                                                                                                               | Karnofsky Performance Scale                                        |                                                            |             |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                       | Descriptions                                                       | Percent                                                    | Description |
| 100                                                                                                                                                                                         | Normal, no complaints, no  evidence of disease.                    |                                                            |             |
| Normal activity. Fully active,                                                                                                                                                              |                                                                    |                                                            |             |
| 0                                                                                                                                                                                           | able to carry on all pre-disease  performance without restriction. | Able to carry on normal activity;                          |             |
| 90                                                                                                                                                                                          | minor signs or symptoms of  disease.                               |                                                            |             |
| 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). | Normal activity with effort;                                       |                                                            |             |
| 80                                                                                                                                                                                          | some signs or symptoms of  disease.                                |                                                            |             |
| 1                                                                                                                                                                                           | Cares for self, unable to carry                                    |                                                            |             |
| 70                                                                                                                                                                                          | on normal activity or to do  active work.                          |                                                            |             |
| 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.                             | Requires occasional                                                |                                                            |             |
| 60                                                                                                                                                                                          | assistance, but is able to care  for most of his/her needs.        |                                                            |             |
| 2                                                                                                                                                                                           | Requires considerable                                              |                                                            |             |
| 50                                                                                                                                                                                          | assistance and frequent  medical care.                             |                                                            |             |
| In bed >50% of the time.  Capable of only limited selfcare, confined to bed or chair  more than 50% of waking  hours.                                                                                                                                                                                             | 40                                                                 | Disabled, requires special care  and assistance.           |             |
| 3                                                                                                                                                                                           | Severely disabled,                                                 |                                                            |             |
| 30                                                                                                                                                                                          | hospitalization indicated. Death  not imminent.                    |                                                            |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to  bed or chair.                                                                                    | 20                                                                 | Very sick, hospitalization  indicated. Death not imminent. |             |
| 4                                                                                                                                                                                           | 10                                                                 | Moribund, fatal processes  progressing rapidly.            |             |
| 5                                                                                                                                                                                           | Dead.                                                              | 0                                                          | Dead.       |
appendix e ecog performance status
appendix f new york heart

| Class                                           | Patient Symptoms                             |
|-------------------------------------------------|----------------------------------------------|
| Class I (Mild)                                  | No limitation of physical activity. Ordinary |
| physical activity does not cause undue          |                                              |
| fatigue, palpitation, or dyspnea (shortness     |                                              |
| of breath).                                     |                                              |
| Class II (Mild)                                 | Slight limitation of physical activity.      |
| Comfortable at rest, but ordinary physical      |                                              |
| activity results in fatigue, palpitation, or    |                                              |
| dyspnea.                                        |                                              |
| Class III                                       | Marked limitation of physical activity.      |
| (Moderate)                                      | Comfortable at rest, but less than ordinary  |
| activity causes fatigue, palpitation, or        |                                              |
| dyspnea.                                        |                                              |
| Class IV                                        | Unable to carry out any physical activity    |
| (Severe)                                        | without discomfort. Symptoms of cardiac      |
| insufficiency at rest. If any physical activity |                                              |
| is undertaken, discomfort is increased.         |                                              |
appendix e ecog performance status
appendix g list of potential

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.  
| 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   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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.
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.  
| Month ___________   |                   |                   |                 |          |        |          |
|---------------------|-------------------|-------------------|-----------------|----------|--------|----------|
| Sunday              | Monday            | Tuesday           | Wednesday       | Thursday | Friday | Saturday |
| # of pills_______   | # of pills_______ | # of pills_______ |                 |          |        |          |
| Time ____am/pm      | # of pills_______ | # of pills_______ |                 |          |        |          |
| Time ____am/pm      | # of pills_______ |                   |                 |          |        |          |
| Time ____am/pm      | # of pills_______ |                   |                 |          |        |          |
| Time ____am/pm      | Time ____am/pm    | Time _____am/pm   | Time _____am/pm |          |        |          |
| # of pills_______   | # of pills_______ | # 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      | Time _____am/pm   | Time _____am/pm   |                 |          |        |          |
| # of pills_______   | # of pills_______ | # 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      | Time _____am/pm   | Time _____am/pm   |                 |          |        |          |
| # of pills_______   | # of pills_______ | # 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      | Time _____am/pm   | Time _____am/pm   |                 |          |        |          |
| # of pills_______   | # of pills_______ | # 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      | Time _____am/pm   | Time _____am/pm   |                 |          |        |          |
| Notes:              |                   |                   |                 |          |        |          |
appendix h study medication diary
drug diary for oral dexamethasone

| Record Date and         | Record Dose of      | If dose of any drug was missed or changed,   |
|-------------------------|---------------------|----------------------------------------------|
| Time taken              | Dexamethasone taken | provide a reason                             |
| mg mg mg mg mg mg mg mg |                     |                                              |  
| APPENDIX I: Child-Pugh Classifications      | Points                         |                       |                       |
|---------------------------------------------|--------------------------------|-----------------------|-----------------------|
| Clinical and Lab Criteria                   |                                |                       |                       |
| xx                                          |                                |                       |                       |
| Encephalopathy                              | (grade 0 )                     | (grade 1 or 2)        | (grade 3 or 4)        |
| Mild to moderate                            | Severe                         |                       |                       |
| Ascites                                     | None                           | (diuretic responsive) | (diuretic refractory) |
| Bilirubin (mg/dL)                           | < 2                            | 2-3                   | >3                    |
| Albumin (g/dL)                              | > 3.5                          | 2.8-3.5               | <2.8                  |
| Prothrombin time                            |                                |                       |                       |
| Seconds prolonged                           | <4                             | 4-6                   | >6                    |
| International normalized ratio              | <1.7                           | 1.7-2.3               | >2.3                  |
| GRADE²                                      | DESCRIPTION                    | POINTS                |                       |
| (A)                                         | Mild; well-compensated disease | 5-6                   |                       |
| Moderate; significant functional compromise | 7-9                            |                       |                       |
| B                                           |                                |                       |                       |
| C                                           | Severe; decompensated disease  | 10-15                 |                       |