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musculoskeletal and connective tissue disorders

NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial Neuropathy NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; Pyramidal tract syndrome; Reversible posterior leukoencephalopathy syndrome; Syncope 61 PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS - Epistaxis; Pharyngolaryngeal pain; Pleural effusion; Pulmonary edema; Respiratory, thoracic, and mediastinal disorders - Other (bronchiolitis obliterans)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and subcutaneous tissue disorders - Other (paraneoplastic pemphigus)
VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis NOTE: Rituximab in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
Please refer to the package insert for the comprehensive list of adverse events.
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8.2 definitions 8.2.1 adverse event

Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE 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 it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. An abnormal laboratory value will not be assessed as an AE unless that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.
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8.2.2 significance of an adverse

External adverse events are adverse events experienced by subjects enrolled in multicenter clinical trials at sites other than the site(s) over which the Institutional Review Board has jurisdiction. **Internal adverse events** are adverse events experienced by subjects enrolled at the site(s) under the IRB's jurisdiction for either multicentre or single-center research projects. The significance of AEs is used to describe the patient/event outcome or action criteria associated with events that pose a threat to a patient's life or functioning (i.e., moderate, severe, or life threatening). Based on the National Cancer Institute Guidelines for Cancer Therapy Evaluation Program, severity can be defined by the following grades of events:
**Grades 1** are mild adverse events (e.g., minor event requiring no specific medical intervention, asymptomatic laboratory findings only, marginal clinical relevance).  
**Grades 2** are moderate adverse events (e.g., minimal intervention, local intervention, noninvasive intervention, transfusion, elective interventional radiological procedure, therapeutic endoscopy or operation).  
**Grades 3** are severe and undesirable adverse events (e.g, significant symptoms requiring 62 hospitalization or invasive intervention, transfusion, elective interventional radiological procedure, therapeutic endoscopy or operation).  
**Grades 4** are life threatening or disabling adverse events (e.g., complicated by acute, lifethreatening metabolic or cardiovascular complications such as circulatory failure, haemorrhage, sepsis, life-threatening physiologic consequences, need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation).  
**Grades 5** are fatal adverse events resulting in death.
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8.2.3 serious adverse event definition

Serious AE (SAE) means any untoward medical occurrence that at any dose:
Results in **death**.  
Is **life-threatening** (refers to an AE in which the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe).  
Requires inpatient **hospitalization or prolongation of an existing hospitalization** (see clarification in the paragraph below on planned hospitalizations).  
Results in **persistent or significant disability or incapacity**. (Disability is defined as a substantial disruption of a person's ability to conduct normal life functions).  
Is a **congenital anomaly/birth defect**. Is a **medically important event**. This refers to an AE that may not result in death, be immediately life threatening, or require hospitalization, but may be considered serious when, based on appropriate medical judgment, may jeopardize the patient, require medical or surgical intervention to prevent one of the outcomes listed above, or involves suspected transmission via a medicinal product of an infectious agent. Examples of such medical 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; any organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent.  
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The general term *severe* is often used to describe the intensity (severity) of a specific event; the event itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as *serious*, which is based on patient/event outcome or action criteria described above, and is usually associated with events that pose a threat to a patient's life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3to less than 2000 is considered Grade 3
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
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8.2.4 expectedness

Adverse Events can be Expected or Unexpected.  
An **expected** adverse event is an event previously known or anticipated to result from 63 participation in the research study or any underlying disease, disorder, or condition of the subject. The event is usually listed in the Investigator Brochure, consent form or research protocol.  
An **unexpected** adverse event is an adverse event not previously known or anticipated to result from the research study or any underlying disease, disorder, or condition of the subject.  
8.2.5 Attribution Attribution is the relationship between an adverse event or serious adverse event and the study drug. Attribution will be assigned as follows:
**Definite** - The AE is clearly related to the study drug.  
**Probable** - The AE is likely related to the study drug.  
**Possible** - The AE may be related to the study drug.  
**Unlikely** - The AE is doubtfully related to the study drug. **Unrelated** - The AE is clearly NOT related to the study drug.
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8.3 procedures for reporting all

AEs may be spontaneously reported by the patient and/or in response to an open question from study personnel or revealed by observation, physical examination, or other diagnostic procedures.  
Any clinically relevant deterioration in laboratory assessments or other clinical finding is considered an AE. When possible, signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event. For serious AEs, the investigator must determine both the intensity of the event and the relationship of the event to study drug administration. For serious pretreatment events, the investigator must determine both the intensity of the event and the relationship of the event to study procedures.  
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) and to Celgene Drug Safety from the first dose of study drug through 30 days after administration of the last dost of study drug. Any SAE that occurs at any time after completion of study treatment or after the designated follow-up period that the sponsor-investigator and/or sub-investigator considers to be related to any study drug must be reported to Millennium Pharmacovigilance (or designee) and to Celgene Drug Safety. In addition, new primary malignancies that occur during the follow-up periods must be reported, regardless of causality to study regimen, for a minimum of three years after the last dose of the investigational product, starting from the first dose of study drug. All new cases of primary malignancy must be reported to Millennium Pharmacovigilance (or designee) and to Celgene Drug Safety.
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adverse event reporting

Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting. A copy of the CTCAE Version 4.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  
All appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. All adverse clinical experiences, whether observed by the investigator or reported by the patient, must be recorded, with details about the duration and intensity of each episode, the action taken with respect to the test drug, and the patient's outcome. The investigator must evaluate each adverse experience for its relationship to the test drug and for its seriousness. The investigator must appraise all abnormal laboratory results for their clinical significance. If any abnormal laboratory result is considered clinically significant, the investigator must provide details about the action taken with respect to the test drug and about the patient's outcome.  
64 Since this is an investigator-initiated study, the principal investigator, Dr. Brian Hill, also referred to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any regulatory agency and to the sponsor- investigator's EC or IRB.  
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must also be reported in English to Millennium Pharmacovigilance (or designee):
**Fatal and Life Threatening SAEs** within 24 hours of the sponsor-investigator's observation or awareness of the event All other serious (non-fatal/non-life **threatening) events** within 4 calendar days of the sponsor-investigator's observation or awareness of the event See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance and to Celgene Drug Safety.  
The sponsor-investigator must fax or email the SAE Form per the timelines above. A sample of an SAE Form will be provided.  
The SAE report must include at minimum:
**Event term(s)** **Serious criteria**
**Intensity of the event(s):** Sponsor-investigator's or sub-investigator's determination. Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI CTCAE version specified in the protocol, as a guideline, whenever possible. The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html.  
**Causality of the event(s):** Sponsor-investigator's or sub-investigator's determination of the relationship of the event(s) to study drug administration.  
**Attribution:** Attribution is the relationship between an adverse event or serious adverse event and the study drug. For this study, relationship to all study drugs for each SAE will be determined by the investigator or sub-investigator by responding yes or no to the question: Is there a reasonable possibility that the AE is associated with the study drug(s)?  
Follow-up information on the SAE may be requested by the sponsors of the study.  
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI
CTCAE version used at your institution, as a guideline, whenever possible. The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html.  
Sponsor-investigator must also provide Millennium Pharmacovigilance and Celgene Drug Safety with a copy of all communications with applicable regulatory authorities related to the study product(s), as soon as possible but no later than 4 calendar days of such communication.
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celgene

Celgene Corporation Global Drug Safety and Risk Management Fax: (908) 673-9115 E-mail: drugsafety@celgene.com Suggested Reporting Form:
SAE Report Form (provided by Millennium)
US FDA MedWatch 3500A:
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm Any other form deemed appropriate by the sponsor-investigator
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institutional review board reporting requirements

Investigative sites will report adverse events to their respective IRB according to the local IRB's policies and procedures in reporting adverse events.
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8.4 procedures for reporting drug

If a woman becomes pregnant or suspects that she is pregnant while participating in this study or within 90 days after the last dose, she must inform the investigator immediately and permanently discontinue study drug. The sponsor-investigator must immediately fax a completed Pregnancy Form to the Millennium Department of Pharmacovigilance or designee (see Section 8.3) and to Celgene Drug Safety. The pregnancy must be followed for the final pregnancy outcome. If a female partner of a male patient becomes pregnant during the male patient's participation in this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to the Millennium Department of Pharmacovigilance or designee (see Section 8.3) and to Celgene Drug Safety. Every effort should be made to follow the pregnancy for the final pregnancy outcome. Suggested Pregnancy Reporting Form:
Pregnancy Report Form (provided by Millennium or Celgene)
8.5 **Data Safety Toxicity Committee**
It is the Case Comprehensive Cancer Center's Principal Investigator's responsibility to ensure that ALL serious adverse events are reported to the Case Comprehensive Cancer Center's Data Safety Toxicity Committee. This submission is simultaneous with their submission to the Sponsor or other Regulatory body. The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC Data and Safety Monitoring Plan. 8.6 **Data and Safety Monitoring Plan (DSMP)**
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety Monitoring Plan in accordance with NCI guidelines
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9.0 pharmaceutical information

A list of the adverse events and potential risks associated with the investigational or commercial agents administered in this study can be found in Section 8.0. Agents are listed in alphabetical order.
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9.1 ixazomib

Chemical Name: 2,2'-{2-[(1R)-1-1({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-
5-oxo-1,3,2-dioxoborolane-4,4-diyl}diacetic acid Other Names: MLN9708 Classification: proteasome inhibitor (as the boronic acid)
Molecular Formula: C20H23BCl2N2O9 Mode of Action: proteasome inhibitor Metabolism: hydrolysis, hydroxylation, dehydrogenation and N-dealkylation Product Description: capsule Solution Preparation: NA
Storage Requirements: The container should be stored at the investigative site refrigerated
(36°F to 46°F, 2°C to 8°C). Patients should be instructed to store the medication refrigerated (36°F
to 46°F, 2°C to 8°C) for the duration of each cycle.
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route of administration oral

Drug Procurement: Ixazomib will be supplied for this study by Millennium, a Takeda corporation.  
Drug Accountability: The investigator or designated study personnel are responsible for maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, including study drug accidentally or deliberately destroyed. Under no circumstances will the investigator allow the investigational drug to be used other than as directed by the protocol. If appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the pharmacy section of the investigative site.  
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 67 shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused study drug. Drug destroyed on site will be documented in the study files.
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9.2 lenalidomide

Chemical Name: 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-dione Other Names: NA
Classification: Immunomodulatory agent Molecular Formula: C13H13N3O3 Mode of Action: Immunomodulatory agent Metabolism: rapidly absorbed following oral administration; approximately two-thirds is eliminated unchanged through urinary excretion Product Description: Capsules Solution Preparation: NA
Storage Requirements: Room temperature Stability: Not defined Route of Administration: Oral Drug Procurement: Lenalidomide will be supplied for this study by Celgene. Drug Accountability: The investigator or designated study personnel are responsible for maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, including study drug accidentally or deliberately destroyed. Under no circumstances will the investigator allow the investigational drug to be used other than as directed by the protocol. If appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the pharmacy section of the investigative site.  
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused study drug. Drug destroyed on site will be documented in the study files.
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9.3 rituximab

Other Names: Rituxan ®; MabThera ®, IDEC-C2B8 Classification: Monoclonal antibody 68
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mode of action binding to

Product Description: chimeric murine/human gamma 1 kappa monoclonal antibody
(Chinese hamster ovary [CHO] transfectoma)
Solution Preparation: diluted to a concentration of 1 to 4 mg/mL in polyvinylchloride or polyolefin IV bags containing normal saline or 5% dextrose Stability: Intact vials of rituximab are stored refrigerated at 2 - 8 oC (36 - 46oF). Protect vials from direct sunlight. Once diluted as above, stable for up to 24 hr. at 2 - 8 oC, and at room temperature for an additional 12 hrs. after refrigeration (for a maximum period of 36 hrs.) if protected from light.
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route of administration intravenous slow

Drug Procurement: Rituximab must be obtained from commercial sources.  
Commercially available: Preservative-free injection 10mg/mL, in 10 and 50 mL single-unit vials. Please see Package Insert for further information.  
The cost of this agent will be the subject's responsibility, often covered by medical insurance.
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10.0 correlative / special studies

Predictive biomarkers for response and resistance to biologically targeted agents should improve our ability to personalize therapy by selecting agents most likely to be effective based on the biomarker. No such validated biomarkers exist for indolent non-Hodgkin's Lymphoma, iNHL,
treated with the agents in this study. A set of tissue samples from patients enrolled in this study will be stored on glass slides (tissue microarray or TMA) for future processing for appropriate studies focused on biomarker development simultaneously for DNA, RNA, or protein targets. TMA
provides an ideal method of storing fixed tissue samples so that they can be processed at a future time when more information on prognostic and predictive factors becomes available.
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10.1.2 collection of specimens

Formalin-fixed, paraffin embedded (FFPE) diagnostic tissue biopsies from all patients for whom these are available will have a core removed from the FFPE tissue block and placed into the TMA,
by standard procedures in the Tomsich Pathology Laboratory. The site should prepare the patient block, provide the de-identified number for the study and ship as soon as readily available. Shipment of these samples at ambient temperature is satisfactory.  
The pathology procedure is to perform an H&E stain to order to identify the tumor tissue in the block and have it marked by the pathologist. Tumor cores of 1 mm size will be taken from the marked area(s) by the research tech. For the TMA and duplicate TMA, 4 cores would be required because each TMA would also include a duplicate core. Additional 2-4 cores, depending on the tissue size, would also be collected and saved in a labeled Eppendorf tube for future molecular 69 studies. The TMA will be gradually built and the core locations mapped in a TMA schematic as the tissue specimens arrive in the laboratory.  
Any remaining block can be returned to the site. Please contact Dr. Ondrejka or the research laboratory (Lisa Durkin) with any questions regarding the collection of the specimen:  
  
The site is instructed to ship to the address and label as shown below. Include the name of the study, CASE 1414 on the shipping label. About 24 hours prior to shipment, provide the shipping information to Lisa Durkin, durkinl@ccf.org, and Dr. Ondrejka's medical secretary, Linda Rosa, lrosa@ccf.org.
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10.1.3 handling of specimens

TMA will be stored in the Tomsich Pathology Laboratory in a secure ambient temperature monitored location. All patient tissue must be de-identified prior to placing in the TMA.
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10.1.4 correlative methods

Precise plans for analysis of TMA by immunohistochemistry and/or macromolecule isolation will depend on future knowledge. This correlative is simply to store samples in usable form at this time.
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10.2 flow cytometry on peripheral

Flow cytometry is commonly used to identify and quantitate normal and abnormal circulating lymphocytes. It is sensitive and specific for detecting small numbers of circulating lymphoma cells, as well as providing insight into the host immune response of normal lymphocyte subsets. Baseline evaluation of blood lymphocytes subsets may be a marker of nodal immune response, and the molecular signature of tumor infiltrating cells in lymph node biopsies of patients with follicular lymphoma does provide prognostic information while nodal T-lymphocyte subset evaluation predicts prognosis independently of the Follicular Lymphoma International Prognostic Index (FLIPI). Specifically, CD4+ T-cells and interfollicular CD68+ cells (macrophages) are associated with a poor outcome, while FOXP3+ cells, CD8+ cells, and programmed death 1 (PD-  
70 1) + cells are associated with a good prognosis. We have shown that absolute NK cells at baseline are a prognostic factor in follicular lymphoma. In this study, we will use the immunodeficiency panel as standardly performed in the Tomsich laboratory to assess lymphocyte subsets at baseline and end of treatment. This measures CD3, CD4 and CD8 T cells, NK cells and CD19+ B cells.  
Serial quantitation of remaining circulating lymphoma cells may be an indicator of systemic response and outcome. Minimal residual disease (MRD) refers to submicroscopic disease burden remaining in a patient after therapy for a neoplasm. Attaining a state of undetectable MRD has been shown to correlate with longer progression free survival and decreased relapse risk in some diseases. Whether this is merely a marker for those with more responsive disease or whether more therapy aimed at eradicating MRD is beneficial is not always clear. Some patients will achieve a state of no MRD after therapy; however, as time from end of therapy lengthens MRD may become detectable. Theoretically it is possible to react and treat a patient much earlier before the disease burden increases and the patient becomes more difficult to treat. There are several methods of monitoring MRD. Molecular techniques using polymerase chain reaction can be applied if there is a stable molecular abnormality in the disease, like t(14;18) in follicular lymphoma. In the absence of a recurring translocation, the patient specific clonal V-D-J immunoglobulin gene rearrangement can be assessed, though this is labor and cost intensive. Also it is not clear that the detection of the molecular abnormality with PCR correlates clinically with outcomes. Newer NexGen sequencing methods can also be used to quantitate residual clonal cells
(Adaptiv LymphoSight® assay). Another method of evaluating for MRD is multicolor flow cytometry to detect clonal B cells using cell surface antigens unique to the malignant clone. The ability to evaluate for multiple antigens on the cell allows for accurate identification of a malignant cell in a population of mainly normal cells. Standard flow assays can be adapted for this and validated, but are not routinely done in pathology labs, including at CCF. Standard lymphocyte analysis by flow measures the percentage of B cells, from which an absolute number of B cells can be calculated. In this study we will evaluate residual B cells pre- and post-treatment as potential biomarkers. We will extract and store DNA from these samples for possible future NexGen sequencing assessment of MRD.
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10.2.2 collection of specimens

Blood samples will be drawn into anti-coagulated tubes (see Appendix VI) as per standard procedures. All such samples will be at the time of clinically indicated blood sampling so no extra venipunctures are needed.
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10.2.3 handling of specimens

Blood samples will be sent to the flow cytometry lab of the Tomsich Pathology Laboratory (see Appendix VI) for processing and fluorescent staining and flow cytometric analysis by standard procedures.
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10.2.4 correlative methods

Patients whose blood has no detectable B cells (MRD negative status) will be compared with those in whom B cells remain detectable in terms of PFS and OS to determine if this can be an early marker of outcome for patients with iNHL treated with the treatment regimen in this protocol. Baseline T cell subset levels will be correlated with outcome as before.
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11.0 study parameters and calendar

| Parameter                                                                                                                            | Prestudy1                           | Day 1 of Every  Cycle (+/- 3 days)   | Cycle  1-3 Day 8   | Cycle  1-3 Day 15   | Cycle  1-3 Day 22   | Restaging12 and Follow-up14   |
|--------------------------------------------------------------------------------------------------------------------------------------|---------------------------|--------------------------------------|--------------------|---------------------|---------------------|-------------------------------|
| Assignment of FLIPI scores2                                                                                                          | X                         |                                      |                    |                     |                     |                               |
| Notation of GELF criteria2                                                                                                           | X                         |                                      |                    |                     |                     |                               |
| History and Physical examination                                                                                                     | X                         | X                                    | X                  |                     |                     |                               |
| Performance Status                                                                                                                   | X                         | X                                    | X                  |                     |                     |                               |
| Tumor Measurements by Physical  Exam (if applicable)                                                                                 | X                         | X                                    | X                  |                     |                     |                               |
| CBC and Differential                                                                                                                 | X3                        | X                                    | X4                 | X4                  | X4                  | X                             |
| Serum Chemistries  (electrolytes, AST, ALT, total  bilirubin, direct bilirubin5 ,  creatinine, glucose, alkaline  phos, and calcium) | X7                        | X                                    | X                  | X                   | X                   |                               |
| LDH                                                                                                                                  | X                         | X                                    | X                  | X                   | X                   |                               |
| Beta-2-microglobulin                                                                                                                 | X                         |                                      |                    |                     |                     |                               |
| HIV testing                                                                                                                          | X                         | X                                    |                    |                     |                     |                               |
| Uric acid                                                                                                                            | X                         | Cycles 3-6 only if >                 | X                  | X                   |                     |                               |
| ULN prior cycle                                                                                                                      |                           |                                      |                    |                     |                     |                               |
| Monoclonal protein determination13                                                                                                   | X                         | X13                                  | X13                |                     |                     |                               |
| X                                                                                                                                    |                           |                                      |                    |                     |                     |                               |
| (up to 90  days)                                                                                                                     |                           |                                      |                    |                     |                     |                               |
| Bone marrow aspirate biopsy If not known to be involved                                                                              | After cycle 12  if in CR6 |                                      |                    |                     |                     |                               |
| Pregnancy test (for women of childbearing potential)7                                                                                                                                      | X7                        |                                      |                    |                     |                     |                               |
| Hepatitis B surface antigen and  core antibody testing8                                                                              | X8                        |                                      |                    |                     |                     |                               |
| CASE1414 RIXAR Protocol Version 8, 4/11/2022                                                                                         | 72                        |                                      |                    |                     |                     |                               |
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11.1 study parameters and schedule

| T4, TSH                                            | X   | Day 1 Cycle 7 only     | X15            |    |    |
|----------------------------------------------------|-----|------------------------|----------------|----|----|
| Immunodeficiency Panel16                           | X   | Day 1 cycle 7 only     | After cycle 12 |    |    |
| Creatinine clearance                               | X   | calculated             |                |    |    |
| CT Chest, Abdomen, and Pelvis;  Neck (if involved) | X9  | After cycles 3 and 610 |                |    |    |
| PET/CT Scan                                        | X9  | After cycle 1211       |                |    |    |
| Baseline Symptoms/AE  Evaluation17                 | X   | X                      | X              | X  | X  |  
On rituximab treatment days 8 and 15 of cycle 1, patients will be assessed by a nurse for toxicity, and CBC, serum chemistries, LDH and uric acid will be performed. Pre-study parameters can be up to 30 days prior to start of treatment, except bone marrow aspirate and biopsy can be up to 90 days, if not known to be positive for lymphoma  
1. Cycles are every 28 days. Patients may be evaluated in the office more frequently at the physician's discretion.  
2. Yes/No should be entered for each criterion of GELF and FLIPI, as well as absolute calculation of FLIPI-1 and FLIPI-2. (See Appendix V).  
3. At baseline: please record the absolute lymphocyte count.
4. Cycles 2 and 3 for dose escalation cohorts *only* : CBC and differential is required on Days 8, 15 and 22. Other labs ( chem, LDH, UA ) should be done days 8, 15 of cycle 1 only, not in cycles 2-3 5. Direct bilirubin is required only if total bilirubin is elevated. 6. Repeat bone marrow biopsy core and aspirate only if positive at baseline and otherwise meets criteria for CR.  
7. Within 2 weeks of start of induction treatment. For definition of woman of childbearing potential (WOCBP) see lenalidomide
(Revlimid®)REMS program. Before starting lenalidomide: WOCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10-14 days prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug. The subject may not receive study drug until the Investigator has verified that the results of these pregnancy tests are negative. Female subjects will be warned that sharing study drug is prohibited and will be counseled about pregnancy precautions and potential risks of fetal exposure. During study participation and for 28 days following discontinuation from the study: WOCBP with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study 73 discontinuation, and at days 14 and 28 following discontinuation from the study. In addition to the required pregnancy testing, the Investigator must confirm with WOCBP that she is continuing to use two reliable methods of birth control at each visit. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood. Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be discontinued during this evaluation. If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male study subject during study participation, study drug must be immediately discontinued.  
8. Patients must be tested for hepatitis B surface antigen within 6 weeks of randomization. Liver function tests and quantitative PCR assay for HBV levels in serum to be performed monthly until 6 months following last rituximab dose for HBcAb positive patients. Further, consideration should be given to treat such patients with anti-viral prophylaxis (e.g., lamivudine 100mg po QD) prior to, during, and for 6 months after completion of the last dose of rituximab. Patients who are positive for HBsAg
(surface antigen) are not allowed to enroll on study.  
9. If PET/CT scan has been done, do not need separate diagnostic quality CT unless the only measurable disease is in the mesentery and not measurable without oral contrast, in which case CT abdomen/pelvis with oral/IV contrast should be done prior to treatment.  
10. CT scans (chest/abdomen/pelvis; neck if involved) should be done to evaluate response between days 22 - 29 after cycle 3 and after cycle 6. If a PET/CT is done, then CT does not need to be done, unless the only initially measurable disease was in the mesentery and not measurable without oral contrast, in which case CT abdomen/pelvis with oral/IV contrast should be done.  
11. Once patient enters PET negative complete remission, then only CT's (chest/abdomen/pelvis, include neck if previously involved) need to be done in follow-up 12. Restaging will be 8 - 12 weeks after day 1 cycle 12 (or after day 1 of last cycle of treatment if stopped early). Repeat bone marrow only if it was involved prior to treatment and patient otherwise meets criteria for CR.  
13. Monoclonal protein (M-protein) blood determination includes: serum immunofixation, quantitative IgG, IgA, IgM,. If M-protein is detected, the abnormal value will be checked every other cycle beginning with cycle 2, and during follow-up at months 6, 12, 24, 36, 48 and 60 (each  30 days) or until the patient comes off the study 14. FOLLOW-UP: per clinical standards, generally every 3 months for 2 yearsor as clinically indicated, with: History and Physical examination, Performance Status, Tumor Measurements by Physical Exam (if applicable), CBC and Differential, Serum Chemistries and LDH. CT [Chest, Abdomen, and Pelvis, Neck if previously involved] at months 6, 12, and 24(each 30 days). Follow-up visit and CT schedule should count from end of treatment restaging scan. Once the patient has disease 74 progression or otherwise meets criteria for treatment failure, patient can be followed for survival by telephone or other contact without in-person visit or protocol-mandated CT scans.  
15. Thyroid functions at baseline, pre- cycle 7, at re-staging and once 6 months later 16. Immunodeficiency Panel: One anti-coagulated (prefer purple-top) tube sent to Tomsich Flow laboratory. See Appendix VI for details. Draw at baseline, before cycle 7 and again at 17. Baseline Symptoms and AE assessments should be done on days 8 and 15 for Cycle 1 only. For Cycles 2 and 3, assessments will be performed on Day 1.
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12.0 measurement of effect non-hodgkin

NOTE: These criteria are based on the Revised Response Criteria for Malignant Lymphoma, (Cheson et al., Journal of Clinical Oncology, 2007, 25:579-586). The criteria use the following categories of response as described by the working group: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD). In the case of stable disease, follow-up assessments must have met the SD criteria at least once after study entry at a minimum interval of six weeks. The following guidelines are to be used for establishing tumor measurements at baseline and for subsequent comparison:
The six largest dominant nodes or extranodal masses must be identified at baseline.  
If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant. If there are more than 6 involved nodes or extranodal masses, the 6 largest dominant nodes or extranodal masses should be selected according to the following features: a) they should be clearly measurable in at least two perpendicular measurements; b) they should be from as disparate regions of the body as possible; and c) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
Measurements for all dominant nodes and extranodal masses will be reported at baseline.  
Measurements on non-dominant nodes are not required.  
The lymph nodes or extranodal masses selected for measurement should be measured in two perpendicular diameters, one of which is the longest perpendicular diameter. The lymph nodes should be measured in centimeters to the nearest one tenth of a centimeter (e.g. 2.0 cm, 2.1 cm, 2.2 cm, etc.)
The two measured diameters of each lymph node site or extranodal mass should be multiplied giving a product for each nodal site or extranodal mass. The product of each nodal site should be added, yielding the sum of products of the diameters (SPD). The SPD will be used in determining the definition of response for those who have less than a complete response.  
12.1 **Complete Response (CR)** Complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy.  
12.1.1 In patients with a typically FDG-avid lymphoma with no pre-treatment PET scan, or for lymphomas for which the PET scan was positive prior to therapy: a posttreatment residual mass of any size is permitted as long as it is PET-negative.
12.1.2 For variably FDG-avid lymphomas without a pretreatment PET scan, or if a pretreatment PET scan was negative: all lymph nodes and extranodal masses must have regressed on CT to normal size (< 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy). Previously involved nodes that were 1.1-1.5 cm in their long axis and >1.0 cm in their short axis prior to treatment must have decreased to < 1 cm in their short axis after treatment.  
12.1.3 The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination, and nodules related to lymphoma should disappear. However, no normal size can
76 be specified because of the difficulties in accurately evaluating splenic and hepatic size and involvement. For instance, a spleen considered normal size may contain lymphoma, whereas an enlarged spleen may not necessarily reflect the presence of lymphoma, but variations in anatomy, blood volume, the use of hematopoietic growth factors, or other causes.  
12.1.4 If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but demonstrating a small population of clonal lymphocytes by flow cytometry will be considered a CR until data become available demonstrating a clear difference in patient outcome.  
NOTE: Complete Remission/unconfirmed (CRu): Using the above definition for CR and that below for PR eliminates the category of CRu.  
12.2 **Partial Response (PR)**
The designation of PR requires all of the following:
12.2.1 A ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses. These nodes or masses should be selected according to the following: (a) they should be clearly measurable in at least 2 perpendicular dimensions; if possible, they should be from disparate regions of the body; (b) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
12.2.2 No increase in the size of other nodes, liver or spleen.  
12.2.3 Bone marrow assessment is irrelevant for determination of a PR if the sample was positive prior to treatment. However, if positive, the cell type should be specified, e.g. large-cell lymphoma or small cleaved cell lymphoma.  
12.2.4 No new sites of disease.  
12.2.5 For a typically FDG-avid lymphoma with no pretreatment PET scan or one that was PET-positive prior to therapy, the post-treatment PET should be positive at any previously involved sites.  
12.2.6 For variably FDG-avid lymphomas/FDG-avidity unknown, without a pretreatment PET scan, or if a pretreatment PET scan was negative, CT scan criteria should be used.  
12.2.7 Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders.  
12.2.8 When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.
77
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12.3 stable disease (sd)

12.3.1 Failing to attain the criteria needed for a PR or CR, but not fulfilling those for progressive disease (see below).  
12.3.2 Typically FGD-avid lymphomas: The PET should be positive at prior sites of disease with no new areas of involvement on the post-treatment CT or PET.
12.3.3 For variably FDG-avid lymphomas/FDG-avidity unknown: For patients without a pretreatment PET scan or if the pre-treatment PET was negative, there must be no change in the size of the previous lesions on the post-treatment CT scan.  
12.4 **Progression (PD) and Relapse**
For determination of relapsed and progressive disease, lymph nodes should be considered abnormal if the long axis is more than 1.5 cm, regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if the short axis is more than 1 cm. Lymph nodes < 1 x < 1 cm will not be considered as abnormal for relapse or progressive disease. Treatment decisions in patients with presumed refractory, relapsed or progressive disease should not be made solely on the basis of a single PET scan without histologic confirmation.  
12.4.1 Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size.
Increased FDG uptake in a previously unaffected site should only be considered relapsed or progressive disease after confirmation with other modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely on the basis of the PET without histologic confirmation.  
12.4.2 At least a 50% increase from nadir in the SPD of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions (e.g. splenic or hepatic nodules). To be considered progressive disease, a lymph node or extranodal mass with a diameter of the short axis of less than 1.0 cm must increase by > 50% and to a size of 1.5 cm x 1.5 cm or more than 1.5 cm in the long axis.  
12.4.3 At least a 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.  
12.4.4 Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems (< 1.5 cm in its long axis by CT).  
12.4.5 Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these response criteria, the spleen is considered nodal disease. Disease that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by 78 imaging studies or physical examination, it is found to be histologically negative.  
12.5 **Duration of Response**
Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.
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12.6 progression-free survival (pfs)

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
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12.7 time to treatment failure

Time to treatment failure (event-free survival) is defined as the time from study entry to first event of disease progression, discontinuation of treatment for any reason, initiation of new treatment, or death.
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12.8 overall survival

Overall survival is defined as the date of study entry to the date of death.
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13.0 records to be kept

A product complaint is a verbal, written, or electronic expression that implies dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who identify a potential product complaint situation should immediately contact MedComm Solutions
(see below) and report the event. Whenever possible, the associated product should be maintained in accordance with the label instructions pending further guidance from a Millennium Quality representative.  
For Product Complaints, Phone: 1-877-N1-POINT (1-844-617-6468)
E-mail: GlobalOncologyMedInfo@takeda.com FAX: 1-800-881-6092 Hours: Mon-Fri, 9 a.m. - 7 p.m. ET(US)
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an SAE form should be completed and sent to Millennium Pharmacovigilance (refer to Section 8.3).  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0
(Adverse Events: List and Reporting Requirements).
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13.1 data reporting

79 The Overture and OnCore™ Databases will be utilized, as required by the Case Comprehensive Cancer Center, to provide data collection for both accrual entry and trial data management. Overture and OnCore™ are Clinical Trials Management Systems housed on secure servers maintained at Case Western Reserve University. Access to data through Overture and OnCore™ is restricted by user accounts and assigned roles. Once logged into the Overture or OnCore™ system with a user ID and password, Overture and OnCore™ define roles for each user which limits access to appropriate data. User information and password can be obtained by contacting the OnCore™ Administrator at OnCoreregistration@case.edu.  
Overture and OnCore™ are designed with the capability for study setup, activation, tracking, reporting, data monitoring and review, and eligibility verification. This study will utilize electronic Case Report Form completion in the Overture database. A calendar of events and required forms are available in Overture and OnCore™.
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13.2 regulatory considerations

The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 21 CFR parts 56 & 50), state or local laws.
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13.2.1 written informed consent

Provision of written informed consent must be obtained prior to any study-related procedures. The Principal Investigator will ensure that the subject is given full and adequate oral and written information about the nature, purpose, possible risks and benefits of the study as well as the subject's financial responsibility. Subjects must also be notified that they are free to discontinue from the study at any time. The subject should be given the opportunity to ask questions and allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in conformance with the institution's standard operating procedures. A copy of the signed written Informed Consent Form must be given to the subject.
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13.2.2 subject data protection

In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject must sign an authorization to release medical information to the sponsor and/or allow the sponsor, a regulatory authority, or Institutional Review Board access to subject's medical information that includes all hospital records relevant to the study, including subjects' medical history.
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13.2.3 accessing electronic medical records

The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of all documentation of adverse events, records of study drug receipt and dispensation, and all IRB
correspondence for as long as needed to comply with national and international regulations. No records will be destroyed until the Principal Investigator confirms destruction is permitted.
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13.2.5 audits and inspections

Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 80 Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits or inspections, including source data verification. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents to determine whether these activities were conducted, and data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and any applicable regulatory requirements.
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14.0 statistical considerations

14.1 **Populations for Analysis**
Patients in Phase 1B considered evaluable for toxicity to determine MTD will include those that complete the first 4 week cycle or those removed for DLT in cycle 1. Patients evaluable for response will be those who complete 3 cycles of therapy and at least one post-baseline response assessment or those who are taken off study for progressive disease.  
14.2 **Methods**
Phase 1 B consisted of up to three dose levels (See Section 6). 12 patients total were enrolled and the MTD was determined to be at DL3.  
Phase 2 will follow as one expansion cohort treated at the MTD which was determined to be DL3. It will comprise of 18 patients evaluable for response, with follicular lymphoma A
maximum of 24patients will be available for this portion of the analysis, 18 from expansion cohorts, and 6 who were treated at the RP2D.
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14.4 early stopping toxicity

If 2 of the first 6 patients treated at the RP2D experience an SAE, or if subsequently the fraction of patients experiencing SAE exceeds 1/3, accrual to the trial will be halted and trial continuation reassessed with the Case Comprehensive Cancer Center's Data Safety Toxicity Committee in concert with the Millennium Pharmacovigilance and Celgene Drug Safety Departments.
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references

1. Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy Studies. in 52nd *ASH Annual Meeting and Exposition*, 2010. 116(21): p.  
abstr 1813.  
2. Gupta, N., M. Saleh, and K. Venkatakrishnan. *Flat-Dosing Versus BSA-Based Dosing* for MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic
(PK) Analysis of Pooled Data From 4 Phase-1 Studies in *53rd ASH Annual Meeting and* Exposition. 2011. San Diego, CA; p. abstr 1433 3. Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with solid tumors; Updated phase 1 results in *Head and Neck Symposium*. 2012. Phoenix, AZ
4. Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 17th *EHA Annual Congress.* 2012. Amsterdam, the Netherlands.  
5. Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in *ASCO Annual Meeting*. 2012. Chicago, Illinois.  
6. Kumar S, et al. *Weekly Dosing of the Investigational Oral Proteasome Inhibitor* MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose- Escalation Study In *53rd ASH Annual Meeting and Exposition*; 2011 10-13 Dec; San Diego, CA; p. abstr 816..  
7. Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study in *54th ASH Annual Meeting and Exposition*. 2012. Atlanta, Georgia.  
8. Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, Georgia.  
9. Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in previously untreated multiple myeloma patients (pts):
Evaluation of weekly and twice-weekly dosing in 17th *EHA Annual Congress.* 2012.  
Amsterdam, the Netherlands.  
10. San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in combination with melphalan and prednisone in patients with previously untreated multiple myeloma: a phase 1 study in 17th *EHA Annual Congress.* 2012. Amsterdam, the Netherlands.  
11. Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study In: 53rd ASH Annual Meeting *and Exposition*; 2011 10-13 Dec; San Diego, CA; p. abstr 301.  
12. Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, et al. *Phase I study of twice weekly* dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO Meeting Abstracts) 2012;30(15 suppl):abstr 8017.  
13. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al. *Weekly* Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with 82 Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 DoseEscalation Study In: *53rd ASH Annual Meeting and Exposition*; 2011 10-13 Dec; San Diego, CA; p. abstr 816.  
14. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study. Journal of Clinical Oncology 2012 ASCO Annual Meeting Proceedings 2012:Abstract 8034.  
15. Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al.  
Safety and P*harmacokinetics of Weekly MLN9708, an Investigational Oral Proteasome* Inhibitor, Alone and in Combination. Clinical Lymphoma Myeloma and Leukemia 2013;13(Supplement 1):S154; abstr P-230 16. *Common Terminology Criteria for Adverse Events (CTCAE)*. 2010.
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appendices

Appendix I **Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status**  
Grade **Description**  
| 0   | Normal activity. Fully active, able to carry on all predisease performance  without restriction                                                                                       |
|-----|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1   | Symptoms but ambulatory. Restricted in physically strenuous activity, but  ambulatory and able to carry out work of a light or sedentary nature (e.g.,  light housework, office work) |
| 2   | In bed < 50% of the time. Ambulatory and capable of all self-care, but  unable to carry out any work activities. Up and about more than 50% of  waking hours.                         |
| 3   | In bed > 50% of the time. Capable of only limited self-care, confined to bed  or chair more than 50% of waking hours.                                                                 |
| 4   | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair                                                                                 |
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appendix ii cockcroft-gault equation

Creatinine Clearance = CrCl For males:
CrCl = (140–age [years]  weight [kg])
72  (serum creatinine [mg/dL])
For females:
CrCl = 0.85 (140–age [years]  weight [kg])
72  (serum creatinine [mg/dL])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31-41. Appendix III **List of Potential Medication Interactions Affected by CYP3A4 Systems** of Enzymes Potential Medication Interactions Affected by CYP3A4 Systems of Enzymes  
| List of Known CYP3A4 Inhibitors   |                  |                        |
|-----------------------------------|------------------|------------------------|
| Indinavir                         | Erythromycin     | Diethyldithiocarbamate |
| Nelfinavir                        | Fluconazole      | Fluvoxamine            |
| Ritonavir                         | Grapefruit Juice | Gestodene              |
| Clarithromycin                    | Verapamil        | Imatinib               |
| Itraconazole                      | Diltiazem        | Mibefradil             |
| Ketaconazole                      | Cimetidine       | Mifepristone           |
| Nefazodone                        | Amiodarone       | Norfloxacin            |
| Saquinavir                        | Chloramphenicol  | Norfluoxetine          |
| Suboxone                          | Boceprevir       | Starfruit              |
| Telithromycin                     | Ciprofloxacin    | Telaprevir             |
| Aprepitant                        | Delaviridine     | Voriconazole           |  
| List of Known CYP3A4 Inducers   |                 |
|---------------------------------|-----------------|
| Efavirenz                       | Phenobarbital   |
| Nevirapine                      | Phenytoin       |
| Barbiturates                    | Pioglitazone    |
| Carbamazepine                   | Rifabutin       |
| Glucocorticoids                 | Rifampin        |
| Modafinil                       | St. John's Wort |
| Oxacarbazepine                  | Troglitazone    |
appendix iv patient pill diary
case1414 daily pill diary

Dear Subject / Legal Guardian, Thank you for participating in this clinical research study. As part of this research study, we are asking that each day you record in this diary information about the date and time of each dosing of study medication. Bring this diary with you to each appointment until the diary is collected by the study site staff.
appendix iv patient pill diary
instructions for taking lenalidomide (days

Take your medication at approximately the same time in the morning every day.  
Swallow lenalidomide capsules whole with water at the same time each day. Do not break, chew or open the capsules.  
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. If it is missed for the entire day, it should not be made up.  
INSTRUCTIONS FOR TAKING IXAZOMIB (DAYS 1, 8, 15 OF EACH 28-DAY CYCLE)
Swallow ixazomib capsules whole, with water. Do not break, chew, or open the capsules.  
Ixazomib should be taken on an empty stomach (no food or drink) at least 1 hour before or at least 2 hours after food. Each capsule should be swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) of water should be taken with the capsules.  
Missed doses can be taken as soon as you remember if the next scheduled dose is 72 hours or more away. A double dose should not be taken to make up for a missed dose. If you vomit after taking a dose, do not repeat the dose. Resume dosing at the time of the next scheduled dose.  
GENERAL INSTRUCTIONS
If you did not take your daily dose, please write down why in the space provided.  
If you experience side effects, please write these down in the space provided as well. Call your nurse if you have any questions about taking either medication.  
Name of Site Contact: ____________________________ Phone Number: _____________________
Return this diary at the end of every cycle to site staff.  
| Day                                                      | Date                                   | Time Pills                        | Dose                  | Indicate Which Pill Taken   |    |              |          |                                                                                     |
|----------------------------------------------------------|----------------------------------------|-----------------------------------|-----------------------|-----------------------------|----|--------------|----------|-------------------------------------------------------------------------------------|
| Taken                                                    | Taken                                  | (Place "X" in Corresponding  Box) | Comments/Side Effects |                             |    |              |          |                                                                                     |
| Month                                                    | Day                                    | Year                              | AM                    | PM                          | mg | Lenalidomide | Ixazomib | Reason for missed doses or any side  effects you have when taking the  medications. |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
| 23                                                       | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
| 24                                                       | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
| 25                                                       | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
| 26                                                       | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
| 27                                                       | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
| 28                                                       | No study medication taken on this day. |                                   |                       |                             |    |              |          |                                                                                     |
appendix iv patient pill diary
appendix v risk factors gelf

To meet GELF criteria, patient must have at least one criterion:
Nodal or extranodal mass > 7 cm At least 3 nodal masses: each > 3.0 cm in longest dimension Systemic symptoms due to lymphoma or B symptoms Splenomegaly with spleen > 16 cm by CT scan Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or peritoneal serious effusion due to lymphoma (irrespective of cell content)
Leukemic presentation (> 5.0 x 109/L malignant circulating follicular cells)
Cytopenias (absolute neutrophil count < 1.0 x 109/L, hemoglobin < 10 gm/dL, and/or platelets
<100 x 109/L).
appendix iv patient pill diary
flipi

Each patient should be assessed for the presence or absence of the following 5 adverse prognostic factors (adverse factor in italics):
1) Age (*> 60 years* vs. 60 years or less) 2) Ann Arbor stage (*III-IV* vs. I-II) 3) Hemoglobin level (*< 120 g/L* vs. 120 g/L or higher)
4) Number of nodal areas ≥ 5 or less; see figure below)
5) Serum LDH level (*above normal* vs. normal or below)
Each patient should then be assigned into one of the following 3 risk groups:  
  
low risk (0-1 adverse factor)
intermediate risk (2 factors) poor risk (3 adverse factors) Nodal map according to FLIPI model.  
Solal-Celigny P, et al. Blood 2004; 104:1258-1265; and Buske C, et al. Blood. 2006;108:1504-150
appendix iv patient pill diary
flipi-2

An updated analysis of the FLIPI was reported (FLIPI-2). This analysis was completed on 832 follicular lymphoma patients treated from 2003 through 2005, of who the majority received rituximab-based therapy. Five clinical factors were identified as being correlated with survival. Three of the parameters were different than the original FLIPI (FLIPI-1), while two were similar (i.e., anemia and older age).  
Each patient should be assessed for the presence or absence of the following 5 adverse prognostic factors (adverse factor in italics):
1) Age (*> 60 years* vs. 60 years or less) 2) Hemoglobin level (< *120 g/L* vs. 120 g/L or higher)
3) β2-microglobulin (*above normal* vs. normal or below)
4) Largest involved lymph node (*> 6 cm* vs. 6cm or lower)
5) Bone marrow (*involved* vs. not involved)
Federico M, et al. J Clin Oncol 2009; 2.  
Appendix VI: Blood Specimen Handling One tube of EDTA anti-coagulated blood (purple top) will be drawn at baseline, with day 1 cycle 7 lab draw and at re-staging after cycle 12, at a regularly scheduled venipuncture time. The tube will be labeled with the patient information and a study specific requisition will be attached to the specimen. The specimen will be delivered to the Tomsich Reference Laboratory. The blood specimen and requisition form must be received and processed within 48 hours by the Tomsich flow cytometry lab, available Monday through Friday. If drawn at Cleveland Clinic, samples will be sent by the same mechanism as for standard blood tests. If drawn at University Hospitals, tubes can be sent with the regularly scheduled Cleveland Clinic daily lab pick up at 2085 Adelbert Road Cutting Room 231(Andrew Wing of Bishop) which runs Monday through Friday. Samples need to be at the designated pick-up spot by 2:45pm. If missed Monday through Thursday, samples will be picked up the next day. If delivered after 2:45pm on Friday, samples will not be able to be run. The Immunodeficiency (CDC) Panel will be run and reported in SunQuest.