appendix b iwc response criteria
performance status criteria

| IWC+PET-Based                                                                              |                                                                    |
|--------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| Response                                                                                   |                                                                    |
| Designations                                                                               | Description                                                        |
| CR by IWC with a completely negative PET                                                   |                                                                    |
| CR                                                                                         | CRu, PR, or SD by IWC with a completely negative PET and a         |
| ngative BMB if positive prior to therapy                                                   |                                                                    |
| PD by IWC with a completely negative PET and CT abnormalities                              |                                                                    |
| (new lesion, increasing size of previous lesion) > 1.5 cm (> 1.0 cm in                     |                                                                    |
| the lungs) and negative BMB if positive prior to therapy                                   |                                                                    |
| CRu                                                                                        | CRu by IWC with a completely negative PET but with an              |
| indeterminate BMB                                                                          |                                                                    |
| PR                                                                                         | CR, CRu, or PR by IWC with a positive PET at the site of a         |
| previously involved node/nodal mass                                                        |                                                                    |
| CR, CRu, PR, or SD by IWC with a positive PET outside the site of a                        |                                                                    |
| previously involved node/nodal mass                                                        |                                                                    |
| SD by IWC with a positive PET at the site of a previously involved                         |                                                                    |
| node/nodal mass that regressed to < 1.5 cm if previously> 1.5 cm, or                       |                                                                    |
| < 1 cm if previously 1.1-1.5 cm                                                            |                                                                    |
| SD                                                                                         | SD by IWC with a positive PET at the site of a previously involved |
| node/nodal mass (i.e., residual mass)                                                      |                                                                    |
| PD                                                                                         | PD by IWC with a positive PET finding corresponding to the CT      |
| abnormality (new lesion, increasing size of previous lesion)                               |                                                                    |
| PD by IWC with a negative PET and a CT abnormality (new lesion,                            |                                                                    |
| increasing size of previous lesion) of < 1.5 cm (< 1.0 cm in the lungs)                    |                                                                    |
| Abbreviations: IWC+PET, International Workshop Criteria plus positron emission tomography; |                                                                    |
| CR, complete response; BMB, bone marrow biopsy; CT, computed tomography; CRu,              |                                                                    |  
unconfirmed complete response; PR, partial response; SD, stable disease; PD, progressive disease.  
APPENDIX C
Data Reconciliation  Listing Investigator Sponsored Study Amgen ISS Category 2 Transmittal Form Carfilzomib 20159838 / IST-CAR-547 Amgen NASCR,
To Phone No: Z (805) 447-5390 AMGEN ISS PROTOCOL \#:
Sponsor: Taussig Cancer Center- CASE COMPREHENSIVE
CANCER CENTER
Fax No: (805) 449-4522 Sponsor Contact Name: _  
| Fax No:   |
|-----------|
| Phone No  |  
Date:
Use this form as a cover page ONLY for Data Reconciliation line listings.  
Fax transmission contents:
To be sent in regular intervals per contractual agreement:
- Data Reconciliation Line Listing Period from to DAAAAAAAA
D DALLINGYYY
\# of Reports Submitted:
For multi-country studies please indicate countries of transmitted report origin:
Total \# of pages in this transmission, including cover page:
appendix d comprehensive list of
version 1 9/6/2013

Updated treatment calendar Updated dose levels Updated DLT criteria Updated management of study drug toxicities Added acyclovir to study treatment as antiviral prophylaxis
appendix d comprehensive list of
version 2 5/27/2014

Added more information regarding Cardiac Monitoring under the dose reduction/dose delay sections ( Section 7)
appendix d comprehensive list of
version 3 7/14/2014

Clarification that Filgrastim may be substituted if pegfilgrastim is not available.  
Specification indicating that DLT data will be recorder during study cycle 1 of treatment (
Additional lab tests were removed from cycle 2-6, day 8 The included tracked version of the protocol provides a more comprehensive view of the revisions made.
appendix d comprehensive list of
version 4 1/5/2015

Specify what procedures would occur on day 8 and 9 of each cycle for dose levels 2-4.  
The screening period was extended from 12 days to 28 days.  
The IB was updated to include additional risk information. Information previously in section 6.4.8 "Myelodysplastic Syndrome and Acute Myeloid Leukemia (heading title and text) was replaced with
"Posterior Reversible Encephalopathy Syndrome.  
Updated table and associated text for adverse drug reactions was also added.
appendix d comprehensive list of
version 5 2/24/2015

Replaced ICEPLEX terminology to MODAPLEX terminology throughout document - Added inclusion criteria 4.1.2 - Patients must have radiographically measureable disease -
Deleted inclusion criteria 4.1.5 - Life expectancy >6 months in the opinion of and documented by investigator -
Updated Research Coordinator contact in Section 5.0 - Registration -
Added DLT wording and clarified information for patients in dose levels >= 2 in Section 7.1 - Hematologic Toxicity and in Table 5 -
Updated Section 10.1.1.3.4 - The MODAPLEX System - to add Qiagen information - Updated Section 10.1.3 - Collection of Specimens - changing number of sections on slides requested, adding additional slide information, and added contact information. - Updated Section 10.1.4 - Handling of Specimens -
Added information about return of slides and added Section 10.1.4.1 - Site Shipping Instructions -
Replaced Calendar and Calendar Key in Section 11.2 to make it more readable and added superscripts to further clarify which procedures are required for Dose Levels 2-6 - Corrected typographical and formatting errors throughout the document
appendix d comprehensive list of
version 6 8/28/2015

Removal of Dr. Brian Bolwell as list of co-investigators Addition of Christopher D'Andrea as co-investigator Increase from 3-month to 6-month for follow-up visit window. Vital signs including: blood pressure, pulse, respiratory rate and temperature. (dose levels 2-6 only)
Protocol amended to indicate that grade 2,3 and 4 (not just grade 3-4 ) nonhematologic toxicity (except fatigue or anorexia lasting < 7 days or Grade 3 nausea and/or vomiting that persists for < 2 days following appropriate supportive care or non-clinically significant grade 3 electrolyte abnormalities that have been corrected) that is treatment-related must return to a grade 1 or better prior to continuing treatment. In the case of recurrence of grade 2 non-hematologic toxicity, continuation on the study will be at the discretion of the principal investigator.  
Window of time for MUGA or echocardiogram extended to be within 6 months prior to administration of protocol therapy unless there is clinical evidence for new cardiac symptoms within period of time since the cardiac assessment.  
Duration of therapy modified to indicate that: "In the absence of treatment delays due to adverse events, treatment may continue for 6 cycles or until one of the following criteria applies:
Unacceptable treatment related toxicity, NCI CTC AE version 4.0 Grade 2, 3 or 4 that fails to recover to baseline or < Grade 3 in the absence of treatment within 4 weeks].  
Steroid premedication clarified to include repeat dexamethasone in with all subsequent treatments if infusion reactions occur in cycle 1, day 1 unless being given as part of rituximab pre-medication Exit PET and CT scan to be obtained between 4-8 weeks after cycle 6, day 1. (not 42-50 days)
Exclusion criteria clarified to indicate : Known CNS involvement by lymphoma. Patients at high risk for secondary CNS involvement but without neurologic symptoms suspected to be due to lymphoma are allowed to be enrolled and receive intrathecal chemotherapy including but not limited to methotrexate, cytarabine and glucocorticoids. Patients who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on study at the discretion of the principal investigator.  
Any DLT as defined in Section 6.2 will result in a dose reduction. In the event of day 8±1 laboratory testing reveals an ANC <100/mm3, hemoglobin <6.5g/dL, or platelets nadir <25,000/mm3 for patients in dose level 4, carfilzomib dosing will be held on days 8 and 9 of the current cycle and reduced to one dose level lower on day 1 of the subsequent cycle, provided that the day 1 parameters are met (ANC ≥ 1200/mm3 and platelets ≥ 75,000/mm3). Should the patient develop a recurrent DLT as defined in Section 6.2, a 2nd dose reduction of carfilzomib will be required. Treatment can resume after allowing recovery to the day 1 criteria assuming treatment has not been delayed for more than 2 weeks. Otherwise, the study drugs must be discontinued (see Criteria for Discontinuation of Study Drug, section 3.4.1.)
Off treatment visit: CT and PET scan to be obtained between 4-8 weeks after cycle 6, day 1. For patients receiving adjuvant or post-chemotherapy radiation treatment, PET and/or CT can be deferred until after completion of radiation.  
Calendar updated Reporting to sponsor (Amgen) updated
appendix d comprehensive list of
version7 11/5/2015

Added specific section in Inclusion Criteria 4.1.1 to indicate where the Hans Algorithm is located in the protocol.  
Removed specific steroid information in Inclusion Criteria 4.1.3.  
Clarified when Carfilzomib will be administered in Section 6.1.1 (after Rituximab).  
Updated the Study Parameters and Calendar in Section 11 to ensure procedures are consistently listed in each location.  
Updated personnel who will access EMR for CCF in Section 13.2.2.  
Corrected typos and formatting errors throughout document.
appendix d comprehensive list of
version 8 4/13/2016

Updated hemoglobin from 9.0 g/dl to 7.0 g/dl in section 4 Updated acyclovir dosing in table 2 Updated nurse contact for SAE reporting Increased window to 14 days for follow up visits
appendix d comprehensive list of
version 9 5/10/2016

Updated Prednisone dosing to days 3-7 Added CMC to D8 for dose level 4 Updated study calendar to include con meds and baseline symptoms
appendix d comprehensive list of
version 10 9/9/2016

Updated Creatinine Clearance from 60 to 45 Clarified that Modaplex testing is not a requirement for screening
appendix d comprehensive list of
version 11 2/1/2017

Added NCT\# to cover page, removed Dr. Smith as Co-I Updated dose level 4 (carfilzomib)
Added dose level 5 Updated study calendar (only safety labs needed for D8 on dose levels 4 and 5)
Visit on D9 is no longer required Update RN contact for SAE reporting Updated DLT section to include dose level 5 Clarified that OnPro is acceptable for pegfilgrastim administration Removed modaplex testing
appendix d comprehensive list of
version 12 2/27/2017

This is an administrative updated for clerical error noted in protocol amendment 11. Updating table on pages 5 and 20 to correct error on dose level 4. Carfilzomib will be administered at 20 mg/m2 in Cycle 1 followed by 45 mg/m2 for cycles 2-6.
appendix d comprehensive list of
version 13 2/1/2018

Updating RP2D throughout protocol Removing dose modification guidelines for Vincristine, allowing for physician discretion given frequency of peripheral neuropathy (section 7.2.1 and Table 6- Management of Neuropathy).  
Changing contact for SAE's from RN to Regulator Coordinator Clarifying collection and handling of specimens (sections 101.3 and 10.1.4)
Updating screening window to 28 days, this was previously listed in change history but was not executed in the protocol Adding 90 day window for screening bone marrow biopsy Making interim PET scan optional because this is not used for disease assessment Adding Florida as a participating site Updating Onyx to Amgen throughout protocol for consistency, Onyx was acquired by Amgen in 2015.  
Updating SAE reporting contact information and providing coversheet in Appendix D
appendix d comprehensive list of
version 14 4/10/2018

Adding physician and sponsor-investigator discretion on dose reducing Carfilzomib in the event of any toxicity.  
Excluding patients of direct Asian-Pacific (China, Japan, Taiwan, Singapore, Republic of Korea, and Thailand) ancestry due to a safety notice that was released by Amgen
appendix d comprehensive list of
version 15 8/1/2018

Removed previous standard of care procedures for Rituxan administration Added an ECHO at the 6 month follow up visit Updated section on contraception use for males and females
appendix d comprehensive list of
version 16 11/14/2018

Made Day 8 labs optional Added Roswell Park as a sub-site Clarified inclusion criteria Updated eligibility criteria to include 1 cycle of prior treatment for DLBCL
within 60 days of enrollment Added HIV testing during screening Added address for correlative samples Updated Sub-text on the calendar to match protocol
appendix d comprehensive list of
version 17 2/18/2020

Exclusion: now allows low risk, fully treated melanoma Now allows for sponsor approval for ANC abnormalities due to BM infiltration Clarified acyclovir inconsistancies: Acyclovir to start C1D1 Removed specific language on rituximab administration, updated to "per institutional guidelines" Updates screening window for patients with SOC R-CHOP to also include anything 14 days prior to their SOC R-CHOP (does not include the scans, those don't have a specified window)
Allows for either a CT or PET to be omitted in patients with SOC R-CHOP as long as there is evidence of measureable disease and available TM for response assessment BMB can be waived by sponsor if BM staging and FISH are available from another type of biopsy SOC R-Chop should be considered a cycle. Patients should receive 1 cycle RCHOP, then 5 cycles of CR-CHOP. A 6th Cycle of CR-CHOP is allowed per investigator discretion (7 total cycles)
Interim scans should be done after 3 cycles of CR-CHOP no matter if they received SOC R-CHOP. So for some patients scans may be done 4 total treatments.  
Extending scan window from 28 to 42 days for those who begin with CR-CHOP
Extending scan window to 56 days prior to SOC therapy for those who begin with R-CHOP
Removed appendix B - no longer applicable Clarified EOT visit is 4-8 weeks from D1 of last cycle of treatment Clarification that patients who progress should only be followed for survival