8 correlative / special studies
protocol 10691 dated 27 aug

| Syndrome                                  |                                                                                                                      |                                        |
|-------------------------------------------|----------------------------------------------------------------------------------------------------------------------|----------------------------------------|
| Metabolic                                 | Criteria for Classification of                                                                                       | Criteria for Classification of         |
| Laboratory Tumor Lysis Syndrome           | Clinical Tumor Lysis Syndrome                                                                                        |                                        |
| Abnormality                               |                                                                                                                      |                                        |
| Hyperruricemia                            | Uric acid > 8.0 mg/dl (475.8 umol/liter)                                                                             |                                        |
| in adults or above the upper limit of the |                                                                                                                      |                                        |
| normal range for age in children          |                                                                                                                      |                                        |
| Hyperphosphatemia                         | Phosphorus > 4.5 mg/dl (1.5 mmol/liter)                                                                              |                                        |
| in adults or > 6.5 mg/dl (2.1 mmol/liter) |                                                                                                                      |                                        |
| in children                               |                                                                                                                      |                                        |
| Potassium > 6.0 mmol/liter                | Cardiac dysrhythmia or sudden death                                                                                  |                                        |
| Hyperkalemia                              | probably or definitely caused by                                                                                     |                                        |
| hyperkalemia                              |                                                                                                                      |                                        |
| Hypocalcemia                              | Corrected calcium < 7.0 mg/dl                                                                                        | Cardiac dysrhythmia, sudden death,     |
| (1.75 mmol/liter) or ionized calcium      | seizure, neuromuscular irritability                                                                                  |                                        |
| < 1.12 (0.3 mmol/liter)                   | (tetany, paresthesias, muscle                                                                                        |                                        |
| twitching, carpopedal spasm,              |                                                                                                                      |                                        |
| Trousseau's sign, Chvostek's sign,        |                                                                                                                      |                                        |
| laryngospasm, or bronchospasm),           |                                                                                                                      |                                        |
| hypotension, or heart falure probably     |                                                                                                                      |                                        |
| or definitely caused by hypocalcemia      |                                                                                                                      |                                        |
| Acute kidney injury 1                     | Not applicable                                                                                                       | Increase in the serum creatinine level |
| of 0.3 mg/dl (26.5 µmol/liter) (or a      |                                                                                                                      |                                        |
| single value > 1.5 times the upper        |                                                                                                                      |                                        |
| limit of the age-appropriate normal       |                                                                                                                      |                                        |
| range if no baseline creatinine           |                                                                                                                      |                                        |
| measurement is available) or the          |                                                                                                                      |                                        |
| presence of oliguria, defined as an       |                                                                                                                      |                                        |
| average urine output < 0.5 ml/kg/hr       |                                                                                                                      |                                        |
| for 6 hrs                                 |                                                                                                                      |                                        |
| t                                         | The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × |                                        |
| (4-albumin in grams per deciliter).       |                                                                                                                      |                                        |  
t
Acute kidney injury is definited as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 µ mol per liter) or a period of oliguia lasting 6 hours or more.  By definition, if acute kidney injury is present, the patient has clinical tumor lysis syndrome.  Data about acute kidney injurt from Levin at al.  
In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same Note:
24-hour period within 3 days before the start of therapy or up to 7 afterward.  Clinical tumor lysis syndrome requires the presence of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death.
13.7appendix g. template for protocol
retain this template for your

Please provide a list of changes from the previous IRB-approved version of the protocol. The list shall identify by page and section each change made to a protocol document with hyperlinks to the section in the protocol document. All changes shall be described in a point-by-point format (ie, Page 3, section 1.2, replace 'xyz' and insert 'abc'). When appropriate, a brief justification for the change should be included.  
| Item           | Section   | Page(s)   | Change   |
|----------------|-----------|-----------|----------|
| 1. 2. 3. 4. 5. |           |           |          |  
E
13.8Appendix H. Drug Order Form for Venetoclax
13.7appendix g. template for protocol
shipment order for clinical studies

| Submit completed form to: supplies.team@abbvie.com           |                           |         |                                        |         |
|--------------------------------------------------------------|---------------------------|---------|----------------------------------------|---------|
| Name of Requestor                                            | Date of request           |         |                                        |         |
| Telephone                                                    | Deliver to site by (date) |         |                                        |         |
| Study                                                        | Delivery restrictions     |         |                                        |         |
| Study as in Clinicopia                                       |                           |         |                                        |         |
| Investigator                                                 | RIC#                      | Site ID | Address / Phone # if not in Clinicopia | Country |
| Note : Unused spaces on this form (below) may be left blank. |                           |         |                                        |         |  
| Check all that appl   |             |          |          |
|-----------------------|-------------|----------|----------|
| Lot Number            | Description | Quantity | d mat mo |  
1. Clinical Drug Supplies to be Shipped 2. Ancillary Materials to be Shipped  
| Earliest Allowable Expiry (minimum 60 days from date of request):   | Check all that apply    |            |
|---------------------------------------------------------------------|-------------------------|------------|
| MMID                                                                | AUDX3 O N               |            |
| Description                                                         | Quantity                | y complete |
|                                                                     |                         |            |
|                                                                     |                         |            |  
3. Additional Items to be Shipped Bioretention Letter Blindbreakers - Numbers to be shipped: Randomization Envelopes - Numbers to be shipped:
4. Additional Comments:
──
■  
E
13.9Appendix I. Drug Order Form for Ibrutinib
13.7appendix g. template for protocol
ist drug order form

For PCYC Office Completion only Form Received Date:
Received by:
CSRF\#.  
Local Site Protocol ID:
CTMS \#
13.7appendix g. template for protocol
to request additional drug please

Please note that drug requests received before 12:00 (PST) will be shipped out the same day and requests after 12:00(PST) will be shipped the next business day. Orders are not shipped on Fridays or holidays.  
PI Name:
Is this request for a subsite?  
If yes, please provide sub-investigator name:
Date of Request:
/ /  
| Requestor Information             |                                                                |                    |
|-----------------------------------|----------------------------------------------------------------|--------------------|
| Study Pharmacist Name             |                                                                |                    |
| Institution                       |                                                                |                    |
| Address                           |                                                                |                    |
| Phone Number                      |                                                                |                    |
| Email                             | Shipping Information (if different from Requestor)             |                    |
| Receiver Name                     |                                                                |                    |
| Institution                       |                                                                |                    |
| Address                           |                                                                |                    |
| Phone Number                      |                                                                |                    |
| Email                             | Please use the table below to determine the number of bottles: |                    |
| Ibrutinib dosage                  | 30-day supply                                                  |                    |
| 420 mg                            | 1 x 92 capsule bottle                                          |                    |
| 560mg                             | 1 x 120 capsule bottle                                         |                    |
| 840mg                             | 2 x 92 capsule bottles                                         |                    |
| Current                           | Number of                                                      |                    |
| Inventory                         | Amount                                                         | Need-By Date       |
| Study Drug Requested              | Enrolled/Active Patients                                       |                    |
| on Site                           | Requested                                                      |                    |
| (Bottles)                         | (dd/mm/yyy)                                                    | as of Request Date |
| (Bottles)                         |                                                                |                    |
| PCI-32765 PO Hard Gelatin Capsule | /                                                              |                    |
| (140 mg-92 capsules per bottle)   | I I                                                            |                    |
| PCI-32765 PO Hard Gelatin Capsule | I I                                                            | /                  |
| (140 mg-120 capsules per bottle)  |                                                                |                    |  
- yes - no
13.7appendix g. template for protocol
13.10 appendix j. drug diary

Instructions: The bottles with the study drug, ibrutinib, should be stored at room temperature and should not be stored in the bathroom. Please do not freeze or refrigerate the study drug. You will take 420 mg of study drug (3 x 140-mg capsules) by mouth once a day with 8 ounces (240 mL) of water (**do not take with grapefruit juice or Seville orange juice**). The capsules should be swallowed intact. Do not open capsules or dissolve them in water. Each dose (**all 3 capsules**) should be taken at least 30 minutes before eating and at least 2 hours after a meal, at around the same time each day. If a dose is missed, it can be taken up to 6 hours after the scheduled time with a return to the normal schedule the following day. If it has been more than 6 hours, the dose should be skipped and you must take the next dose at the scheduled time the next day. The missed dose will not be made up and all the capsules from the missed dose must be returned to the clinic or hospital at the next visit. Please complete the form attached when a dose is missed or reduced. The purpose of this form is to help you keep track and remember when/why a dose was missed or reduced. For each day a dose is missed or reduced, complete the **date** it was missed or reduced and specify the **reason** for the missed or reduced dose. If you experience any abnormal symptoms while taking the study drug, you can also record them on the attached form. It is mandatory that you return this form and your bottles of the study drug to the study staff at each visit to the clinic or hospital.  
E  
| PATIENT DRUG DIARY - IBRUTINIB                                                         |                |
|----------------------------------------------------------------------------------------|----------------|
| Site #                                                                                 | Patient #:     |
| Date Dispensed                                                                         | Date  Returned |
| PI Name Initial here to confirm that the drug has been maintained at room temperature. |                |  
Initial here to confirm that no doses of the study drug were missed or reduced. Initial here to confirm that no extra doses of the study drug were taken by mistake.  
| DIARY FOR MISSED OR REDUCED DOSES OF IBRUTINIB Number of  capsules taken if  Missed or  Reduced   |                      |                               |          |
|---------------------------------------------------------------------------------------------------|----------------------|-------------------------------|----------|
| Date Dose is  Missed or  Reduced                                                                  | Reason for Missed or | Abnormal Symptoms             |          |
| Reduced Dose                                                                                      | (if applicable)      |                               |          |
| Example: 10/1/2016                                                                                | 0                    | Not feeling well              | Nauseous |
| Example: 10/1/2016                                                                                | 2                    | Forgot to take all 3 capsules |          |
13.11 appendix k. drug diary
venetoclax study drug dosing instructions

1. Take 1 dose of Study Drug, by mouth every day, within 30 minutes after completion of breakfast or your first meal of the day.  
a. Drink 1 glass of water (approximately 8 oz or 240 mL) when you take your Study Drug.  
b. Do NOT chew or crush the Study Drug tablets; tablets must be swallowed whole. c. Use all medication within a bottle before opening another bottle of the same dose strength. Bottle may contain more tablets than are needed. Return all bottles (including empty and partially full) to the clinic.  
2. Record the doses you take in the Daily Calendar:
a. **Record dose information daily:**
1) Record Week of treatment. 2) Record the Date (Month/Day/Year). 3) Record your current dose. 4) Record the time that you took your dose. 5) Record whether your dose was taken within 30 minutes after completion of breakfast or your first meal of the day.  
Note: Store study drug supplies as listed on the label. Keep out of the reach of children.  
| Subject Number: WEEK_____DOSING DETAILS   | WEEK_____DOSING DETAILS                  | WEEK_____DOSING DETAILS                  |               |                    |               |
|-------------------------------------------|------------------------------------------|------------------------------------------|---------------|--------------------|---------------|
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:______:_____ am pm          |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |  
| Subject Number: WEEK_____DOSING DETAILS   | WEEK_____DOSING DETAILS                  | WEEK_____DOSING DETAILS                  |               |                    |               |
|-------------------------------------------|------------------------------------------|------------------------------------------|---------------|--------------------|---------------|
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:______:_____ am pm          |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               | | Subject Number: WEEK_____DOSING DETAILS   | WEEK_____DOSING DETAILS                  | WEEK_____DOSING DETAILS                  |               |                    |               |
|-------------------------------------------|------------------------------------------|------------------------------------------|---------------|--------------------|---------------|
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:______:_____ am pm          |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               | | Subject Number: WEEK_____DOSING DETAILS   | WEEK_____DOSING DETAILS                  | WEEK_____DOSING DETAILS                  |               |                    |               |
|-------------------------------------------|------------------------------------------|------------------------------------------|---------------|--------------------|---------------|
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:______:_____ am pm          |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |
| Date:___/___/_____                        | Dose:______mg                            | Date:___/___/_____                       | Dose:______mg | Date:___/___/_____ | Dose:______mg |
| Time of dose:_____:_____ am pm            | Time of dose:_____:_____ am pm           | Time of dose:_____:_____ am pm           |               |                    |               |
| Dose within 30 min of first meal? Yes No  | Dose within 30 min of first meal? Yes No | Dose within 30 min of first meal? Yes No |               |                    |               |