summary of changes
4.0 treatment plan

Protocol agent will be administered on an inpatient basis. Reported adverse events and potential risks are described in Section 5.0 and Section 6.1.16. No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the participant's malignancy.  
The final product is autologous CD34+ cells transduced with a triple combination of antiHIV genes that will be re-suspended in participants' serum, cryopreserved and then thawed and infused directly into central vein of the participants though a central catheter, 1 day after finishing their conditioning chemotherapy. Different number of non-transduced, unmanipulated product will be co-infused similarly according to the study cohort.  
Autologous CD34+ cells isolated via clinical grade magnetic cell separation from mobilized peripheral blood apheresis products of HIV-1 lymphoma participants will be transduced with a 1TAX lentiviral vector carrying a triple combination of anti-HIV genes, tested and cryopreserved. CD34+ cell isolation, transduction, and qualification of the final product will be carried out in the UC Davis GMP facility following established Standard Operating Procedures (SOPs) and appropriate Quality Control (QC) and Quality Assurance (QA). The final product will be tested for identity, viability, purity, sterility, absence of mycoplasma and endotoxin, and for integrated transgene copy numbers per genome. A Certificate of Analysis (COA) will be generated (see Section 6.1). After completed testing, the autologous, cryopreserved product will be thawed and used for infusion into the HIV1 lymphoma participant who has undergone a conditioning regimen.
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4.1 hsc mobilization and peripheral

Prior to stem cell mobilization, eligibility and suitability of the autologous donor will be confirmed based on the screening data and the individual institution guidelines. The infectious disease profile and the rest of the blood donor test will be performed with FDA licensed blood donor tests. In all patients, ART will be withheld 3 days prior and during stem cell collection. This is to decrease the possibility of ART therapy to interfere with the transduction of stem cells before transplant. The stem cell mobilization regimen will be based on the individual participant's need, decided by the transplant physician. Both chemo mobilization and/or growth factor mobilization is allowed. HSC/progenitor cells will be collected by participating institutions, according to the institutional standards. The quality, as well as the quantity, of stem/progenitor cells may be different in each collection. While it is difficult to assess the quality of stem cells, their quantity can be easily measured by the number of CD34 cells at the end of each day collection.  
We aim to collect a minimum of 5 x 106 CD34 cells/kg of body weight of the recipient (ideally 10 x 106 CD34 cells/kg).  
Assignment of the mobilized stem cells for the transduced group and the non-transduced group will be done according to the guidelines below:  
1. *Minimum number of required unmanipulated cells will be collected first (1.5 x 106* CD34 cells/kg of recipient) and will be immediately frozen and stored in harvesting center Progenitor Laboratories as per site SOP.  
2. Additional cells available will be assigned to transduced portion of stem cell collection, which will be transferred to the UC Davis GMP facility by courier in temperature controlled transport containers, undergo CD34+ cell selection and transduction culture, followed by freezing and storage in the GMP facility. We prefer to receive the samples on the same day but they can be held for up to 24 hours and shipped with the next day collection based on the communications of the transplant physicians in the collection facility and the PI or Co-PI of the study.
Stem cell collection goals: Ideally, we aim to collect 10 x 106 CD34+ cells/kg of body weight of the recipient (for both manipulated and unmanipulated product). A minimum of 5 x 106 CD34+ cells/kg of body weight of the recipient is needed to proceed with the study. 1.5 x 106 CD34 cells/kg of body weight of the recipient will be used as the *unmanipulated* product and will be frozen. The rest of the product will be used for stem cell transduction.  
Additional cells can be collected and stored after the target number for CD34 (10 x 106 CD34+ cells/kg) is achieved based on the discretion of the subject's transplant physician and in consultation with the study principal investigator. These cells can be given to the patient, but the ratio of total manipulated to unmanipulated cells needs to follow the guidelines in Table 4-A. The collection will continue until we achieve our collection targets. Table 4-Abelow provides the dose of *transduced* versus *untransduced* cells in each cohort of the study.  
| Minimum Number of  Transduced/  Untransduced Cells  Acceptable. CD34  cells/kg   | Range for Number of  Transduced Cells /  Unmanipulated Cells.  CD34 cells/kg   |                  |                             |
|----------------------------------------------------------------------------------|--------------------------------------------------------------------------------|------------------|-----------------------------|
| Ratio of Transduced                                                              |                                                                                |                  |                             |
| Cohort Level                                                                     | Versus Untransduced  Stem Cells.                                               |                  |                             |
| 1                                                                                | 1:1                                                                            | 1 X 106 :1 X 106 | 1 to 5 X 106 : 1 to 5 X 106 |
| 2                                                                                | 5:1                                                                            | 2 X 106 :1 X 106 | 2 to 5 X 106 :1 X 106       |
| 3                                                                                | 1:0                                                                            | 2 X 106 : 0      | 2 to 10 X 106 : 0           |
| 3+ expansion                                                                     | 1.0                                                                            | 3 x106 : 0       | 3 to 10 X 106 : 0           |
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4.2 agent administration 4.2.1 preparative

All participants enrolled in this protocol will be hospitalized, in all clinical centers, in accordance with the procedures for recipients of HSCT as defined by the treating institutions. They will receive BEAM or R-BEAM regimen as a standard of care preparative regimen administered per institutional guidelines. Physicians may use their discretion and institutional guidelines in determining the appropriate body weight (actual, adjusted, or ideal) for the conditioning regimen dose calculation. The BEAM and R-BEAM regimens for this study are comprised of the following intravenous medications:
- BCNU  
- Cytarabine (Ara-C);
- VP-16
- Melphalan - Participants with B cell Lymphoma may be administered rituximab prior to chemotherapy and post-transplant. Biosimilar agents are permitted at the investigator's discretion.
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4.2.2 stem cell infusion

For the first 2 cohorts, both *transduced* and *un-manipulated* product will be infused within 4 to 24 hours of each other at day 0, intravenously:  
- The *transduced* product will be transported from the GMP facility of UC Davis, stored at the BMT unit of participating facilities and thawed in the BMT unit and immediately infused into the participants.  
o The stem cell lab at participating facilities will be receiving the frozen product via overnight courier, in a temperature-controlled transport container, prior to the start of the conditioning regimen.  
- The *un-transduced* product will be stored at the participating facilities stem cell laboratories, thawed in the BMT unit and immediately infused into the participants, 4 to 24 hours after the infusion of transduced product is concluded.
Again, both procedures, including the route and duration of infusion, will be in accordance with the procedures for recipients of HCT as defined by the treating institution.  
After DSMB approval, Participants in the third cohort will be administered **only**
transduced product. All the sites will follow site SOPs for thawing and infusing the transduced product, which will be coordinated before the start of the trial. In case of non-engraftment, the back-up product stored at the respective site will be infused. The number of cells infused to each participant depends on the cohort that the participant is enrolled in and is mentioned in Table 4-A above. The number of cells in the transduced products is based on CD34 counts after transduction of the stem cells and before freezing.
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4.2.3 antibiotic prophylaxis

All participants during transplant will receive antiviral (acyclovir or valacyclovir), antifungal (fluconazole) and anti-Pneumocystis jiroveci prophylaxis based on each institution guidelines/preference. Antiviral and anti-Pneumocystis jiroveci prophylaxis will be continued for a minimum of one year and 6 months, respectively, after transplant. Antifungal prophylaxis will be continued for 30 days post-transplant. All prophylactic therapy will be restarted during ART withdrawal.  
4.2.4 Antiretroviral therapy
Antiretroviral therapy will be stopped during transplant only for participants with excessive nausea or vomiting and for participants who are not able to take pills due to mucositis, etc. The therapy will be resumed once the transplant team feels confident that the toxicities are resolved, and participant has adequate oral intake. Potential interaction of ART with some of the chemotherapy agents and potential negative effects on stem cell engraftment and marrow recovery will be avoided by using ART that do not have those interactions or side effects. Participants on zidovudine [AZT, ZDV, Retrovir®, or agents containing zidovudine (e.g., Combivir® and Trizivir®], and efavirenz [Sustiva©, or agents containing efavirenz (e.g., Atripla®)], prior to transplant will be switched at least two weeks before the transplant to an alternative regimen without anticipated drug-drug interactions or myelosuppressive properties based on known viral resistance patterns and/or ART history, such as raltegravir and Truvada (emtricitabine and tenofovir).  
Antiretroviral drugs with long half-lives, such as efavirenz, will be avoided posttransplant in participants' combination therapy; if a drug regimen containing a long half-life drug is stopped, only a single drug will remain in the system for a prolonged period of time, and drug-resistant variants of HIV-1 can emerge very quickly.
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4.3 definition of dose-limiting toxicity

Dose limiting toxicity in the trial is defined as lack of timely engraftment (the collective establishment of a persistent absolute neutrophil count of at least 500/mm3 and platelet count of at least 20,000/mm3 for 3 consecutive laboratory values obtained on different days) within one month post-transplant, or any grade 3 and 4 non-hematopoietic organ toxicity that can be attributed (possibly, probably, or definitely) to lentiviral transduced stem cell transplant, excluding alopecia, or any evidence of clonal expansion and excluding expected toxicities that are associated with the pre-transplant conditioning regimen, regardless of grade (see Appendix X for full list).  
Dose escalation will proceed within each cohort according to the following scheme. Doselimiting toxicity (DLT) is defined above.  
| Number of Participants with  DLT at a Given Dose Level   | Escalation Decision Rule                                                                                                                             |
|----------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0 out of 3                                               | Enter 3 participants at the next dose level.                                                                                                         |
| ≥ 2                                                      | If this threshold is exceeded in cohorts 1 or 2, dose  escalation will be stopped. This dose level will be  declared the maximally administered dose |  
| Number of Participants with  DLT at a Given Dose Level                                                                                                                                                                                                                                                                                                          | Escalation Decision Rule                                                                                                                                                                                                                                                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (highest dose administered).  If 2 participants in the 3rd cohort develop DLT due  to insufficient engraftment, an additional 3  patients will be enrolled in the cohort 3+ with an  increase in minimum number of transduced CD34  cells from 2 to 3.0 X 106 cells/kg of recipient  weight.  If 2 or more DLTs occur in cohort 3+, the trial  will be stopped. |                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| 1 out of 3                                                                                                                                                                                                                                                                                                                                                      | Enter at least 3 more participants at this dose  level. If 0 of these 3 participants experience DLT,  proceed to the next dose level.  If 1 or more of this expansion group suffer DLT,  then dose escalation is stopped, and this dose is  declared the maximally administered dose. Three  (3) additional participants will be entered at the  next lowest dose level if only 3 participants were  treated previously at that dose. |
| ≤ 1 out of 6 at highest dose  level at or below the maximally  administered dose                                                                                                                                                                                                                                                                                | This is generally the recommended phase 2 dose.  At least 6 participants must be entered at the  recommended phase 2 dose.                                                                                                                                                                                                                                                                                                            |
| 4.4                                                                                                                                                                                                                                                                                                                                                             | General Concomitant Medication and Supportive Care Guidelines All concomitant medication, including blood products or general supportive guidelines,                                                                                                                                                                                                                                                                                  |  
All concomitant medication, including blood products or general supportive guidelines, will be addressed by treating physicians and based on the institutional guidelines. Section 4.2.4 explains the details of anti-retroviral therapy (ART) during the study period and in the follow up period. All medications must be reported in the site's source documents from the time of study enrollment in Segment A through the treatment discontinuation visit. All medications will be reviewed and updated in the site's source documents at all visits where indicated in the schedule of evaluations. Only a subset of medications will be reported in the Concomitant Medications CRF as listed below:
- Anti-retroviral  
- Antiviral
- Growth colony stimulation factors (GCSF)
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4.5 duration of therapy

The investigational part of this clinical trial (i.e., infusion of gene modified hematopoietic AMC-097 (Version 9.0) 07FEB2022 60 NCI Version Date *07FEB2022* CLIENT CONFIDENTIAL
stem cells) will occur only once after conditioning regimen administration is concluded.
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4.6 duration of follow up

The initial follow-up period for this clinical trial will be two years post-transplant. For practical reasons, close and complete follow up of the participants needs to be limited. We have decided to use the 2-year limit for the close clinical follow-up since majority of the participants post an autologous transplant have recovered their immune system, and they are in a less risk of opportunistic infections as well as disease relapse after 2 years. However, all participants will be followed for 15 years albeit, in a less frequent and intensive form (every 12 months for years 3-15) for safety, as mandated by FDA for all gene therapy study participants. Additionally, every 12 months for years 3-15 we will request optional blood collections to monitor the patient's HIV and vector parameters in the body for participants that consent to optional studies.
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4.7 withdrawal of participants

Participants will complete protocol treatment with HCT. Following HCT, participants may be withdrawn from the study prior to expected completion of that participant voluntarily or by their physician(s) for safety reasons, failure of the participant to adhere to protocol requirements, participant consent withdrawal. Patients who have progression of lymphoma within 24 months of gene therapy infusion will be followed for correlative studies as outlined in section 7.5.8.1. The goal is to monitor the patient's HIV and vector parameters in the body. If early termination of the study should occur for any of the above-stated reasons, the study doctor(s) will have a discussion with the participant on how to stop safely, such as evaluation for risks from the study drugs, follow-up care, and any other procedures that might be recommended. Even though participants may be withdrawn prematurely from the study, it is imperative to collect at least survival data on such participants throughout the protocol defined followup period for that participant (though careful thought should be given to the full data set that should to be collected on such participants to fully support the analysis). Such data is important to the integrity of the final study analysis since early withdrawal could be related to the safety profile of the study drug. If a participant withdraws consent to participate in the study, attempts should be made to obtain permission to record at least survival data up to the protocol-described end of the participant follow-up period.
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5.0 adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 5.1) and the characteristics of an observed AE (Section 5.2)
will determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting System (CTEP-AERS) **in addition** to routine reporting (via AdvantageEDCSM).  
CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31, and October 31.
summary of changes
5.1 comprehensive adverse events and

5.1.1 Adverse event list for genetically modified hematopoietic stem cells Autologous stem cell transplant is a potentially toxic procedure and can result in multiple side effects. Autologous stem cell transplant is clinically indicated in all the participant of this study and is a part of standard of care for all these patients. **Therefore, in this protocol we will focus on only side effects** attributable (possibly, probably or definitely) to lentivector transduced stem cell transplant, excluding expected toxicities that are associated with the pretransplant conditioning regimen (see Appendix X **for full list). The complete**
product information of commercial chemotherapeutic agents to be administered as part of the protocol for stem cell transplant with BEAM or RBEAM regimen can be found in FDA approved package insert for each agent.  
Side Effects specific to participation in this protocol include but not limited to (see Section 6.1.19 **for additional details):** Blood draw risks Bruising, infection, and minor pain or discomfort comparable to a needle prick. IV inserted in the vein risks Inflammation, pain, bruising, bleeding, or infection.
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stem cell infusion

Problems that may occur during stem cell infusion are usually associated with infusion of DMSO and include low blood pressure, lightheadedness, fainting, fever, chills, tachycardia, bronchospasm, and hypoxia. These are temporary effects that are likely to subside after the infusion.
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allergic reactions

Proteins made from large amounts of non-human (protein) can sometimes lead to future allergic reactions. There is a small amount of a modified protein in the AMC-097 (Version 9.0) 07FEB2022 62 NCI Version Date *07FEB2022* CLIENT CONFIDENTIAL
modified cells for which there is a small chance of allergic reaction, but it is unlikely to be harmful to you even if it occurs. If an allergic reaction occurs, it is more likely that the modified cells will be destroyed. After the cell infusion, blood will be tested for any reaction that could affect the use of these agents in the future, but this reaction would not be directly harmful. This reaction is estimated at about a 4% chance of happening.
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possibility of another cancer or

The lentivirus used to modify the cells does not have the genes needed to reproduce itself, but it is possible in the future that it could combine with other genes in the body, or that it could activate an unknown virus to result in a known or unknown medical problem or disease, including the possibility of another cancer.
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reproductive risks

Since the effects of the proposed treatments on a fetus are unknown, any woman who should become pregnant while on this study will be removed from the study, and another method of treatment will be suggested. If male, the participant must practice effective birth control and must advise their partner to contact their physician should they become pregnant. We request the participants use at least one method of contraception for 3 months post-transplant.
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risk of antiviral therapy withdrawal

Participants may be asked to hold on taking their anti-HIV medications on at least three occasions. First, for 3 days before and during stem cell collection (to avoid the interaction of anti-HIV medications on stem cell transduction). The second time, during and/or immediately after chemotherapy for transplant in participants who cannot tolerate oral intake due to severe nausea/vomiting or mucositis. The third time (only in the third cohort), sometime after the first 6 months after the transplant when their immune system has recovered at least to some extent measured by CD4 T cells, participants in the third cohort will be asked if they would agree to voluntarily hold their anti-HIV medications until the onset of the criteria that will prompt resumption of treatment (see Section 2.4.1). The rationale for the third withdrawal is to expand the anti-HIV-1 immune system. Each time the participant stops anti-HIV medications, there is a potential risk that HIV-1 infection can become reactivated, and suppress their immune system, and make them susceptible to severe and potentially life-threatening infections. Clinicians, including an HIV doctor, will closely monitor the participant's immune system, and will restart their anti-HIV medications as soon as level of viral reactivation and suppression of the immune system reaches certain thresholds accepted by experts in the field. However, this may not completely eliminate the risk of complications.
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unknown risks

The experimental treatments may have side effects that no one knows about yet. The researchers will tell participants of new information that might make participants change their mind about participating in the study.
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5.2 classification of aes by

5.2.1 Adverse Event: Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite).  
5.2.2 Life-threatening Adverse Event: Any AE that places the participant or participant, in view of the Investigator, at immediate risk of death from the reaction.  
5.2.3 Serious Adverse Event (SAE): Any AE occurring at any dose that results in any of the following outcomes: Death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or a congenital anomaly/birth defect.  
5.2.4 Please note for hospitalization - All hospitalizations (or prolongation of existing hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be reported regardless of the requirements for Phase of study, expected or unexpected, and attribution. For example, do not report an admission for pharmacokinetic sampling, but do report an admission for a myocardial infarction.  
5.2.5 Toxicity: Toxicity is a term NOT clearly defined by regulatory organizations.  
Toxicity has been described as an AE that has an attribution of possibly, probably or definitely related to investigational treatment. To minimize confusion the NCI would recommend that the term toxicity NOT be utilized for AE reporting purposes. The CTCAE continues to use the term 'toxicity' because of familiarity.
5.2.6 Unexpected Adverse Event: Any AE that is not listed in available sources including the package insert, the Investigator's Brochure, or the protocol.  
5.2.7 CTEP Adverse Event Reporting System (CTEP-AERS): An electronic system for expedited submission of AE reports.  
5.2.8 Attribution: The determination of whether an AE is related to a medical treatment or procedure. Attribution categories: Definite - The AE is clearly related to the investigational agent. Probable - The AE is likely related to the investigational agent. Possible - The AE may be related to the investigational agent. Unlikely - The AE is doubtfully related to the investigational agent. Unrelated - The AE is clearly NOT related to the investigational agent.
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5.3 expedited adverse event reporting

5.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov). The reporting procedures to be followed are presented in the "CTEP, NCI Guidelines: Adverse Event Reporting Requirements" which can be downloaded from the CTEP home page (http://ctep.cancer.gov). These requirements are briefly outlined in the table below (Section 5.3.3). A 24-hour notification is to be made to AMC ODMC by telephone at 301-2511161, only when Internet connectivity is disrupted. Once Internet connectivity is restored, a 24-hour notification phoned in must be entered electronically into CTEP-AERS by the original submitter at the site.  
5.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the local treating physician. CTEP-AERS provides a copy feature for other e-mail recipients.  
5.3.3 Expedited Reporting Guidelines Use the NCI protocol number and the protocol-specific participant ID assigned during trial registration on all reports. Note: A death on study requires both routine and expedited reporting regardless of causality, unless as noted below. Attribution to treatment or other cause must be provided.  
Death due to progressive disease should be reported as **Grade 5 "General**
disorders and administration site conditions - Disease Progression" under the system organ class (SOC) of the same name. Evidence that the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration associated with a disease process) should be submitted.
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table 5-a phase 1 and

FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
- Death  
- A life-threatening adverse event
- An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours
- A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect.
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the participant or participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR
312.32; ICH E2A and ICH E6).  
ALL **SERIOUS** adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEPAERS within the timeframes detailed in the table below.  
| Hospitalization                                  | Grade 1 and Grade 2 Timeframes   | Grade 3-5 Timeframes    |
|--------------------------------------------------|----------------------------------|-------------------------|
| Resulting in Hospitalization  ≥ 24 hrs           | 10 Calendar Days                 | 24-Hour 5 Calendar Days |
| Not resulting in                                 |                                  |                         |
| Hospitalization ≥ 24 hrs                         | Not required                     |                         |
| Expedited AE reporting timelines are defined as: |                                  |                         |  
- "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
- "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
All Grade 3, 4, and Grade 5 AEs Expedited 10 calendar day reports for:
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period. Effective Date: May 5, 2011
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5.3.4 sae reporting to fda

All SAEs that occur in trial participants following treatment initiation require a report to IND sponsor-investigator within one working day of awareness of the event, or immediately if the events are life-threatening or fatal. Participating institutions will make this report by submitting the Adverse Event Form in AdvantageEDCSM. The AMC ODMC will manage all SAE report submissions to the IND sponsor-investigator in accordance with its agreement with the IND sponsor-investigator, using the applicable forms designated for this purpose. The sponsor-investigator will be responsible for reporting all serious and unexpected suspected adverse drug experiences to the FDA for the IND for this trial. Participating study sites should NOT report SAEs to the FDA. Rather, participating sites should report SAEs to the AMC ODMC, and the sponsor-investigator or his designee will be responsible for reporting to FDA. 5.3.4.1 The study sponsor is required to report certain study events in an expedited fashion to the FDA. These written notifications of adverse events are referred to as IND safety reports. The following describes the sponsor safety reporting requirements by timeline for reporting and associated type of event:
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within 7 calendar days any

- associated with the use of the study drug
- unexpected,
- fatal or life-threatening
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within 15 calendar days any

- associated with the use of the study drug, - unexpected, and - serious, but not fatal or life-threatening
-or-  
- A previous adverse event that was not initially deemed reportable but is later found to fit the criteria for reporting (reporting within 15 calendar days from when event was deemed reportable).
Any finding from tests in laboratory animals that:
- suggests a significant risk for human participants including reports of mutagenicity, teratogenicity, or carcinogenicity.  
5.3.4.2 Additional reporting requirements Sponsors are also required to identify in IND safety reports all previous reports concerning similar adverse events and to analyze the significance of the current event in light of the previous reports.
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5.3.4.3 reporting process

Adverse events may be submitted on FDA Form 3500A, or in a narrative format. If supplied in a narrative format, the minimum information to be supplied is noted above.
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5.4 routine adverse event reporting

All AEs that require expedited reporting via CTEP-AERS must also be reported in routine study data submissions (Adverse Event CRF). Routine reporting of all AEs attributed (possible, probable or definite) to lentivector transduced stem cell transplant, regardless of grade, must be reported on the Adverse Event CRF. Expected toxicities that are associated with the pre-transplant conditioning regimen (see Appendix X for full list) do not require routine reporting. All grade 3 or greater AEs, whether or not attributable to lentivector transduced stem cell transplant, will be recorded on the Adverse Event CRF. Reporting of AEs must begin at the time of stem cell collection.
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5.5 clinical laboratory results

Clinical laboratory results that are outside of the institution's reference ranges must be reported as adverse events if they are deemed clinically significant by the investigator(s). 5.5.1 A clinical laboratory abnormality should be deemed clinically significant if any one of the following conditions is met:  
- Is not an erroneous result as proven by repeat testing, if performed, within 48 hours.  
- The laboratory abnormality is directly attributable to the lentivector transduced stem cell transplant, excluding expected toxicities that are associated with the pre-transplant conditioning regimen (see Appendix X for full list).  
- The abnormality suggests a disease and/or organ toxicity that is new or has worsened from baseline.  
- The abnormality is of a degree that requires additional active management, e.g.,
change of dose, discontinuation of the drug(s), close observation, more frequent follow-up assessments, or further diagnostic investigation.  
- Is associated with a serious adverse event or is otherwise judged by the Investigator to be of significant clinical impact.
In general, a laboratory abnormality that is not clinically significant will be consistent with CTCAE grade 1 (mild) or 2 (moderate) severity, as categorized by the relevant severity description in the Investigations System Organ Class (SOC) or Metabolism and Nutrition Disorders SOC. Investigators must designate laboratory abnormalities that are consistent with grade 3 or greater severity as clinically significant.
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5.6 secondary malignancy

A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to describe the event:
- Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia
[AML])
- Myelodysplastic syndrome (MDS)
- Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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5.7 second malignancy

A second malignancy is one unrelated to the treatment of a prior malignancy (and is **NOT** a metastasis from the initial malignancy). Second malignancies require **ONLY** routine adverse event reporting via CDUS unless otherwise specified.
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6.0 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 5.1. The complete product information of commercial chemotherapeutic agents to be administered as part of the protocol for stem cell transplant with BEAM or R-BEAM regimen can be found in FDA approved package insert for each agent.
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6.1 autologous cd34+ cells transduced

Autologous CD34+ cells transduced with a pre-selective marker and triple combination of anti-HIV genes is an investigational agent supplied to AMC investigators by GMP facility at UC Davis Medical Center.
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6.1.1 description

The final product is autologous CD34+ cells transduced with a triple combination of anti-HIV genes that will be re-suspended in participants' serum, cryopreserved and then thawed and infused directly into central vein of the participant though a central catheter, 1 day after finishing their conditioning chemotherapy. Different number of non-transduced, unmanipulated product will be co-infused similarly according to the study cohort. Autologous CD34+ cells isolated via clinical grade magnetic cell separation from mobilized peripheral blood apheresis products of HIV-1 lymphoma will be transduced with a 1TAX lentiviral vector carrying a triple combination of anti-HIV genes, tested and cryopreserved. CD34+ cell isolation, transduction and qualification of the final product will be carried out in the UC Davis GMP facility following established Standard Operating Procedures (SOPs) and appropriate Quality Control (QC) and Quality Assurance (QA). The final product will be tested for identity, viability, purity, sterility, absence of mycoplasma and endotoxin, and for integrated transgene copy numbers per genome. A Certificate of Analysis (COA) will be generated. After completed testing, the autologous, cryopreserved product will be thawed and used for infusion into the HIV-1 lymphoma participant who has undergone a conditioning regimen.  
6.1.2 GMP manufacturing, transduction, cryostorage and qualification of autologous CD34+ cells
All steps are controlled by Standard Operating Procedures (SOPs), overseen by QC and QA and are performed in a state of the art GMP facility at UC Davis Medical Center by qualified personnel.  
6.1.3 The GMP manufacturing process of the cellular product consists of 7 phases 1. Receipt of donor apheresis product.  
2. CD34+ cell selection. 3. In process testing (cell number, CD34+ analysis, viability). 4. Overnight transduction of the isolated CD34+ cells on a fibronectin matrix in the presence of cytokines (SCF, Flt-3 and TPO).
5. Harvesting of the transduced cells.  
6. Freezing and storage of the transplantable, final product. 7. Qualification of the final product and generation of a COA (cell number, viability, sterility, endotoxin, mycoplasma, number of vector integrants per genome).  
6.1.4 Transfer from the manufacturing facility to the clinical site
The fresh product will be transported to the AMC clinical sites. A validated transport container (Liquid Nitrogen, LN2 dry vapor shipper) will be used that can maintain the LN2 vapor phase temperature for at least 48 hours. Transport to the UC Davis Medical Center clinical site only takes 15 minutes. Transfer from the other sites throughout California will be done by a courier and usually within the same day. The cells will be thawed according to standard bone marrow transplant procedure SOPs and will be infused into the participant. Samples will be tested for viability. A final COA will be generated.
summary of changes
6.1.5 plasmid production

Plasmid release tests: Identity (restriction enzyme digest), purity (Limulus amebocyte lysate (LAL) endotoxin assay), sequence (DNA sequencing). Acceptance criteria: Confirmed identity (restriction enzyme digest with readout on gel, bands at appropriate positions), confirmed purity (endotoxin level below acceptable limit), and DNA base pair sequence of plasmid identical to required sequence.
summary of changes
6.1.6 vector manufacturing

Vector release tests: Sterility (USP 14-day sterility according to 21CFR 610.12), LAL endotoxin assay, mycoplasma PCR, RCL (susceptible cell / cell line transductions), sequence of transferred genes (DNA sequencing), contaminating DNA (VSV-g DNA PCR). Acceptance criteria: Sterility (USP 14 day sterility according to 21CFR 610.12) - no organisms seen, LAL endotoxin level below acceptable limit (less than 0.5 EU/mL), mycoplasma not detected by PCR, RCL not detected by HIV-1 p24 from transduction culture of susceptible cell lines and primary target cells, sequence of transferred gene identical to expected sequence, contaminating DNA within acceptable limits. In addition, stability testing (transducing titer) will be performed annually.
summary of changes
6.1.7 cd34+ cell isolation culture

CD34+ cell isolation: In process tests: Cell count, viability (dye exclusion) and CD34+ analysis using FACS. Acceptance criteria: Viability greater than 70%, CD34+ cell content greater than 70%.
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6.1.8 labeling receiving storage dispensing

Procedure for Labeling and Tracking the Product: The product is tracked and labeled according to FACT approved SOPs available in the clinical stem cell labs.  
The labels used for the product conform to current FACT standards.  
Receipt of Drug Supplies: Shipping of the product is carried out in accordance to current FACT standards. The shipping container allows for controlled temperature (2-8 degrees C) to be maintained within the shipping period, the temperature is tracked using data loggers. The apheresis product slated for transduction is received in the UC Davis GMP facility with appropriate chain of custody documentation and is properly logged. The shipment is acceptable if the temperature was maintained within 2-8 deg C during shipping, and no damage to the container or its contents is visible. Chain of custody documentation is filled in and a copy of it is sent to the center that shipped the product. Transduction of the product begins immediately after receipt.
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6.1.9 stem cell transduction

The Collection of CD34+ cell may take multiple days. The product needed for the un-transduced portion of this protocol will be collected first and will be frozen and stored according to each institution's guidelines. Once the minimum required number of CD34+ cells in the product is collected, the collection for products aimed for transduction will start. The cells will be immediately transduced within 24 hours of collection each day and harvested 48 hours later. After harvest, the transduced cell population will be isolated using clinical grade CD25 antibodies coupled to magnetic beads and then cryopreserved. Multiple apheresis products may need to be collected and transduced until the required number of selected cells has been obtained. An aliquot of transduced, selected cells from each final product will be tested for viability, sterility, endotoxin, mycoplasma, vector copy number, and transduction efficiency post selection. Right before the stem cell infusion, the transduced product will be thawed, and an aliquot will be used from each bag for stability testing.
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6.1.10 storage

The cryopreserved, transduced, and selected products are stored at the cryopreservation facilities of each stem cell lab. The same FACT approved SOPs as used for cryostorage, labeling and tracking of other stem cell products apply and are modified accordingly for these research products. Storage of the products is segregated from other products designated for routine clinical use.
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6.1.11 dispensing criteria for final

- Gram stain - Sterility (USP 14-day sterility according to 21CFR 610.12)  
- LAL endotoxin level
- Mycoplasma by PCR
- Viability (dye exclusion)
- Identity (described below)
- Potency (described below)
- Transduction efficiency (CD25 expression by flow cytometry)
- Number of vector copies (qPCR).  
- Stat viability, 14-day sterility. - Acceptance criteria: Stat viability greater than 70%.14-day sterility - no organisms seen. 14-day sterility is only available after 14 days; a positive culture action plan is followed in case of a positive culture result.
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6.1.12 return 6.1.14 stability 6.1.15

Acceptance criteria: Gram stain and sterility - no organisms seen, endotoxin below acceptable limits (less than 0.5 EU/mL), mycoplasma not detectable, viability greater than 70%, identity and purity-confirmed CD34+ purity greater than 70%, transduction efficiency: 1-99%, number of vector copies: less than 3 per genome. The cryopreserved products are shipped to the centers in an LN2 container. The shipping container allows for controlled temperature (-70 to -80 degrees C) to be maintained within the shipping period, the temperature is tracked using data loggers. Appropriate chain of custody documentation accompanies the shipment. The receiving center fills in the required portion of the chain of custody documentation, downloads the temperature data from the data logger and immediately returns a copy of the filled in document and temperature log to the UC Davis GMP facility. The shipment is acceptable if the temperature was maintained less than -140 degrees C during shipping, and no damage to the container or its contents is visible.  
6.1.13 Criteria for final infused product release tests: (performed by transplant centers after thawing the product). Vector stability will be assessed every year through the following tests: sequencing of transduced cells, transgene rearrangement/deletion PCR, levels of transgene expression, and vector titer. The final product is stable for > 5 years. Final formulation will consist of a CD25+ cell enriched fraction in 70 mL bags containing 40ml total volume containing Normosol supplemented with 15% clinical grade human serum albumin and 10% clinical grade DMSO. The product must be thawed according to institutional cellular product thawing protocols.  
6.1.16 Route of administration
Intravenous infusion according to standard transplant protocols.  
6.1.17 Method of administration Intravenous infusion according to standard transplant protocols.  
6.1.18 Special handling The final CD25+/CD34+ cell product will be shipped frozen in LN2 to the respective AMC site for proper institutional cellular product thawing.  
6.1.19 Side effects No known side effects from 1TAX vector transduced cells according to the preclinical data. 6.1.19.1 Toxicities associated with conditioning regimen Participants will receive BEAM or R-BEAM chemotherapy as a standard of care conditioning regimen for transplant. Therefore, these toxicities will not be discussed as a part of this protocol.  
6.1.19.2 Gene therapy associated toxicities
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monitoring for insertional oncogenesis and

In any gene therapy protocol using integrating lentiviruses there is a theoretical risk of insertional oncogenesis due to Replication Competent Lentivirus (RCL) or random or pseudo-random insertional mutagenesis. The latter could activate proto-oncogenes, inactivate tumor suppressor genes, or activate genes that could lead to cellular dysregulation (e.g., generation of an autocrine signaling loop). Based on our pre-clinical experience (in collectively more than 600 mice) and experience with vectors with very similar backbone in other clinical trials, we do not expect to observe gene therapy induced malignancies. However, we will routinely monitor participants for any evidence of transduced cell clonality. This is particularly important for HSCT based studies for cancer since there is an inherent increased risk of secondary malignancies in these participants (about 5-8%) due to the risk of chemotherapy, both as a treatment for controlling the malignancy and as preparative regimen for the transplant. We will routinely perform LAM-PCR every 3 months for the first 2 years of the study for vector integrants and look for evidence of increasing oligoclonality or monoclonality, defined as a 2-fold increase over two successive time points to >20% of total transduced cells. In the case that we identify oligo or monoclonality, we will initiate clinical and laboratory evaluations, including history and physical exam, blood counts, chemistries and appropriate imaging and bone marrow biopsy (if clinically indicated), sequencing of LAM-PCR product, flow cytometry with immunophenotyping of the cells and cytogenetic analyses. If none detected, then LAM-PCRs monitoring will be extended Q3 months for all participants for additional 2 years with the prospective for lifetime routine monitoring.
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incidental production of replication-competent lentivirus

This is highly unlikely during the vector production phase due to the design of the vector system; however, the vector product will undergo rigorous testing for RCL before release to prevent such a theoretical possibility and the incidental production of replication competent lentivirus after introduction of vector-transduced cells into the participant. RCL testing will also be done for the follow up of participants based on the FDA nonbinding recommendations: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComp lianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm0 78723.pdf
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immune response to foreign trim

In the chimeric TRIM5α anti-HIV gene, there is a 13-amino acid patch, which is foreign to native human TRIM5α. Due to this amino acid sequence, it is possible for an antibody based immune reaction to occur against cells expressing this region. This is highly unlikely in the setting of a myeloablative bone marrow transplant when immune tolerance can be induced even against more prominent antigens such as major or minor HLA antigens. Furthermore, in our preliminary data, no immune stimulation was observed in cells pulsed with this amino acid region. Still, and in accordance with FDA guidelines, we will monitor participant serum for any chimeric TRIM5α antibody production using an ELISA test. Additional testing for cytotoxic T lymphocyte (CTL) reactivity will be performed if the ELISA test is positive. If it occurs, we do not expect a major negative effect in the participants since the immune reaction will most likely delete only transplanted cells that harbor the sequence. In the unlikely situation that the reaction eliminates other transplanted stem cells, the back-up product can be given to the participants.
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6.1.20 availability

The 1TAX vector will be available in sufficient quantity for transduction of all CD34+ cells from all 18 participants enrolled in the clinical trial.
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6.1.21 agent accountability

The product is tracked and labeled according to FACT approved SOPs available in the clinical stem cell labs. The labels used for the product conform to current FACT standards. Shipping of the product is carried out in accordance to current FACT standards. The shipping container allows for controlled temperature (2-8 deg C) to be maintained within the shipping period, the temperature is tracked using data loggers. The apheresis product slated for transduction is received in the UC Davis GMP facility with appropriate chain of custody documentation and is properly logged. The shipment is acceptable if the temperature was maintained within 2-8 deg C during shipping, and no damage to the container or its contents is visible. Chain of custody documentation is filled in and a copy of it is sent to the center that shipped the product. Transduction of the product begins immediately after receipt.
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7.0 clinical and laboratory evaluations

7.1.1 Medical history, history of drug allergies, CDC HIV risk categories, history of current and past anti-retroviral regimens, if available; and history of any prior AIDS-defining conditions. Date of initial lymphoma diagnosis is required, with a copy of the pathology report in the medical record. Current concomitant medication list, including all anti-retroviral, anti-viral, antibiotics, and opportunistic prophylaxis should be obtained (must be on stable ART regimen for at least 3 weeks prior to enrollment in the screening segment).  
7.1.2 Physical examination, including performance status (see Appendix II), vital signs
(height, weight, body surface area), neurological exam, and physical staging of the disease as appropriate for the participant's lymphoma.  
7.1.3 Chest X-ray (CXR)
7.1.4 Staging by a CT or a combined PET + CT is required for this study  
7.1.5 EKG
7.1.6 PFTs; DLCO, FEVI, FVC (within 4 weeks prior to study enrollment) 7.1.7 Cardiac ejection fraction (by 2D ECHO or MUGA scan) (within 4 weeks prior to study enrollment)
7.1.8 Bone marrow biopsy and aspirate with flow cytometry for pathology 7.1.9 Laboratory tests, including:  
7.1.9.1 Assessment for Cytomegalovirus immunoglobulin (CMV IgG) and CMV quantitative PCR.  
7.1.9.2 Assessment for Hepatitis A antibody, Hepatitis B core antibody, Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody, and Hepatitis C antibody (within 3 weeks prior to study enrollment).
If Hepatitis B core antibody or Hepatitis C antibody is positive, complete Hepatitis B DNA PCR and Hepatitis C DNA PCR
7.1.9.3 Assessment for Herpes simplex virus (HSV) 1 & 2 IgG and PCR  
7.1.9.4 Assessment for Toxoplasma immunoglobulin G (IgG) 7.1.9.5 Assessment for Varicella zoster virus immunoglobulin G (VZV IgG)
7.1.9.6 Assessment for Syphilis, Rapid Plasma Reagin (RPR) or Venereal Disease Research Laboratory (VDRL)  
7.1.9.7 Assessment of HIV-1 and Human T-lymphotropic virus antibodies 7.1.9.8 Assessment of Creatinine Clearance (within 3 weeks prior to study enrollment)
7.1.9.9 Complete blood count (CBC) with differential, Platelet Count, comprehensive metabolic panel (CMP), Lactic Acid Dehydrogenase (LDH), and Uric Acid 7.1.9.10 Assessment of CD4 count 7.1.9.12 Serum pregnancy test for women of childbearing potential 7.1.9.13 Assessment of PT/PTT or INR/PTT (within 3 weeks prior to study enrollment)
7.1.10 Optional donation to the AIDS and Cancer Specimen Resource (ACSR). (See Appendix IV for ACSR Informed Consent Form and Appendix III for ACSR Specimen Preparation and Shipping Instructions).  
7.1.11 CCR5-tropism assay (We will use both commercially available assays (i.e.,
phenotypic assay performed by Monogram Biosciences and the genotypic assay performed by Quest Diagnostics) (See Appendix IX).  
7.1.12 Immunology assays (correlative study, see Appendix I and Appendix VII). 7.1.13 DNA monitoring assays (correlative study, see Appendix I and Appendix VII). 7.1.14 Virology assays (correlative study, see Appendix I and Appendix VII). 7.2.1 Medical history, history of drug allergies, history of current and past anti-retroviral regimens, if available; and history of any prior AIDS-defining conditions. Date of initial lymphoma diagnosis is required, with a copy of the pathology report in the medical record. Current concomitant medication list, including all anti-retroviral, anti-viral, antibiotics, and opportunistic prophylaxis should be obtained.  
7.2.2 Physical examination, including performance status (see Appendix II), vital signs
(height, weight, body surface area), neurological exam, and physical staging of the disease.  
7.2.5 Assessment of CD4 count
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7.2 screening evaluations required within

7.1.9.11 Assessment of Quantitative immunoglobulins (IgM, IgG, and IgA) 7.1.9.14 HIV-1 RNA viral load to be assessed by any FDA-approved viral load assay (evaluated at the local laboratory). (The HIV viral load assay must detect at minimum viremia < 50 copies/mL by RT-PCR) (within 6 months prior to study enrollment; see Section 3.1.2.2).  
7.2.4 Complete blood count (CBC) with differential, Platelet Count, comprehensive metabolic panel (CMP), Lactic Acid Dehydrogenase (LDH), and Uric Acid 7.2.6 HIV-1 RNA viral load to be assessed by any FDA-approved viral load assay
(evaluated at the local laboratory). (The HIV viral load assay must detect at minimum viremia < 50 copies/mL by RT-PCR).
summary of changes
7.3 required on the day

7.3.1 Medical history, history of drug allergies, history of current and past anti-retroviral regimens, if available; and history of any prior AIDS-defining conditions. Date of initial lymphoma diagnosis is required, with a copy of the pathology report in the medical record. Current concomitant medication list, including all anti-retroviral, anti-viral, antibiotics, and opportunistic prophylaxis should be obtained.  
7.3.2 Serum pregnancy test for women of childbearing potential. 7.3.3 Basic immune assessment (i.e., CD4, CD8, and IgG) will be collected at the participating site.
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7.4 evaluations during treatment

All the procedures in association with the transplant that are mentioned below will be performed based on each institute clinical protocols and SOPs. See Section 4.0 for the Treatment Plan. 7.4.1 Performance of apheresis procedure.  
7.4.2 Conditioning (BEAM or R-BEAM) regimen to treat HIV-1-related lymphoma. 7.4.3 Treatment of conditioning regimen associated side effects such as nausea, diarrhea, mucositis, neutropenia fever, etc., and, 7.4.4 Prophylactic antibiotic choice and duration for fungal, viral, bacterial, and parasitic infections. Any deviation from the standard of care needs to be reported to the study PI in AdvantageEDCSM and will be reviewed by the AMC DSMB when reviewing all participants on the cohort.
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7.5 post-treatment follow-up evaluations

The schedule of follow up is shown in detail in Appendix I and Table 4-A and is summarized in the table below. During each follow up, in addition to regular history and physical exam, participants will be evaluated for study related side effects, status of their lymphoma and the status of HIV-1 using appropriate tests. Assessments during strategic ART withdrawal will be on a weekly basis and may be performed remotely, as described in Appendix XI. If required clinical and laboratory assessments (physical exam, medical history and medical review, toxicity assessments, CD4/CD8 counts and HIV VL) during ART withdrawal overlap with required post-treatment follow-up evaluations then these assessments do not need to be repeated.  
| Study Visit   | Target Day PostTransplant             |
|---------------|-------------|
| 1 week        | 7 ± 3 days  |
| 2 week        | 14 ± 3 days |  
| Study Visit   | Target Day PostTransplant                                                                                |
|---------------|--------------------------------------------------------------------------------|
| 3 week        | 21 ± 3 days                                                                    |
| 4 week        | 28 ± 3 days                                                                    |
| 6 week        | 42 ± 3 days                                                                    |
| 2 months      | 60 ± 3 days                                                                    |
| 3 months      | 90 ± 3 days                                                                    |
| 4 months      | 120 ± 3 days                                                                   |
| 6 months      | 180 ± 10 days                                                                  |
| 8 months      | 240 ± 10 days                                                                  |
| 10 months     | 300 ± 10 days                                                                  |
| 12 months     | 360 ± 10 days                                                                  |
| 14 months     | 420 ± 20 days                                                                  |
| 16 months     | 480 ± 20 days                                                                  |
| 18 months     | 540 ± 20 days                                                                  |
| 20 months     | 600± 20 days                                                                   |
| 22 months     | 660 ± 20 days                                                                  |
| 24 months     | 720 ± 20 days                                                                  |
| 7.5.1         | Update medical history. History to include concomitant medication changes, and |  
7.5.1 Update medical history. History to include concomitant medication changes, and any signs and symptoms. Adverse event assessment (adverse events must be recorded in AdvantageEDCSM as per Section 5.4).  
7.5.2 Physical examination, including performance status (see Appendix II), vital signs
(height, weight, body surface area), neurological exam at every follow-up visit.  
7.5.3 Toxicity assessment 7.5.4 Assessment of engraftment.  
Note: this assessment will stop after 2 months. However, assessment of anti-HIV1 transduced clonal cell expansion will continue as a part of correlative studies for the entire period of follow-up.  
7.5.5 Restaging by a CT or a combined PET + CT, at 3, 6, 12, and 24 months' time points.  
See Section 8.1 and Section 8.2 for response parameters and frequency of response evaluations.  
7.5.6 For participants with bone marrow involvement by the lymphoma: Bone marrow biopsy and aspirate with flow cytometry in participants to assess marrow as a part of restaging at 3 months and 12 months timepoints.  
7.5.7 Laboratory tests, including:
7.5.7.1 Assessment for Cytomegalovirus by CMV quantitative PCR weekly for the first month post-transplant, and then at 2, 4, and 6 months post-transplant.  
7.5.7.2 Complete blood count (CBC), comprehensive metabolic panel (CMP),
Lactic Acid Dehydrogenase (LDH), and Uric Acid 7.5.7.3 Basic immune reconstitution assays, CD4 and CD8, and IgG levels.  
Performed at 4 weeks post-transplant; and at 2, 3, 4, 6, 8, 10, 12, 18, and 24 months post-transplant.  
7.5.7.4 HIV-1 RNA viral load to be assessed by any FDA-approved viral load assay
(evaluated at the local laboratory). The HIV viral load assay must detect at minimum viremia < 50 copies/mL by RT-PCRHIV viral load will be performed at 4 weeks, 3, 6, 8, 10, 12, 14, 16, 20, and 24 months posttransplant.
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7.5.8 correlative studies

For a complete list of correlative studies and their timeline see the study calendar (Appendix I) and also the tables on correlative section (Appendix VII).
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7.5.8.1 virology studies

Blood samples will be collected at 2 and 10 weeks and then 6, 12- and 24months post-transplant for HIV reservoir characterization. These studies will include quantitative PCR analysis of PBMC-associated HIV DNA, RNA (including unspliced and multiply spliced forms) and 2-LTR circles. In addition, single genome sequencing of HIV gp120 and HIV pol will be performed to understand sequence evolution following transplantation and detection of minority resistance variants. Single-copy HIV from plasma will also be determined at each of these time points.  
7.5.8.2 GI biopsy (optional) will be performed voluntarily at 6 months posttransplant (or when CD4 count reaches above 300 cell/mm3) and will be repeated two months after the first GI biopsy. The University of California San Francisco is conducting a cohort study called SCOPE that also includes an optional intestinal biopsy. The SCOPE study is an observational, prospective study of HIV-1 infected volunteers designed to provide a specimen bank of samples with carefully characterized clinical data. Specimens banked as part of the SCOPE study will be used to examine questions involving virologic, immunologic, and host factors involved in HIV-1 infection, progression, non-progression, response to treatment, control of HIV-1 virus, and evolution of drug resistance. If participants choose to co-enroll in the SCOPE study at the same time as this study and agree to optional GI biopsies, then we will use their intestinal biopsy results for both studies. SCOPE is a separate study and requires a separate consent form. Participation in SCOPE is not a requirement of this study.  
7.5.8.3 DNA and flow cytometry-based monitoring studies and assessment of antiHIV-1 transduced clonal cell expansion and insertional mutagenesis and flow cytometric based assays for CD25 expression on CD34+ lymphoid and non-lymphoid immune cell populations. These studies will be performed at 2 weeks and then, 1, 2, 4, 6, 8, 10, 12, 18, and 24 months post-transplant.  
7.5.8.4 Monitoring for immune response to TRIM5α. These studies will be performed at 1, 2, 6, 12, 18, and 24 months post-transplant.  
7.5.8.5 Monitoring for mixed lymphocyte reactions: to determine whether unmodified, post-SCT PBMC recognize and kill engrafted, modified cells, a mixed lymphocyte reaction will be performed using post-SCT PBMCs obtained when more than 50% drop in chimerism of transduced cells in PB is determined. PBMC will be mixed with pre-SCT modified stem cells (generated from remaining CD34+ depleted CD4+ T cells from pre-SCT leukapheresis). Gene modified cell killing and markers or T and NK cell activation and function will be determined in the ex vivo experiments using flow cytometric analysis.  
7.5.8.6 Immunological studies. These studies will be performed at 3, 6, 12, and 24 months post-transplant.  
7.5.8.7 Optional bone marrow biopsy and aspirate at 3 and 12 months will be performed for research in participants without bone marrow involvement and that consent to optional studies.
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7.6 discontinuation evaluations

7.6.1 Early discontinuation. Participants who discontinue protocol treatment early for any reason should have the following evaluations and laboratory tests within 30 days of discontinuation: 7.6.1.1 History and physical exam and assessment of adverse effect.
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7.6.1.2 laboratory evaluation for cbc

7.6.1.3 CT or PET CT and bone marrow biopsy and aspirate with flow cytometry for participants with bone marrow involvement for documentation of disease staging. See Section 8.1 for response parameters.  
7.6.1.4 Basic immune reconstitution assay (i.e., CD4, CD8 counts and IgG levels). 7.6.1.5 Correlative studies: immune reconstitution, virologic, and specialized immunologic and DNA monitoring studies.  
7.6.1.6 Optional bone marrow biopsy and aspirate for participants without bone marrow involvement that consent to optional studies.  
7.6.2 Off-study evaluations. Participants who complete all treatment per-protocol should have the following evaluations and laboratory tests within 30 days of discontinuation: 7.6.2.1 History and physical exam and assessment of adverse effect. 7.6.2.2 Laboratory evaluation for CBC, LDH, uric acid, and CMP. 7.6.2.3 CT or PET CT and bone marrow biopsy and aspirate with flow cytometry for participants with bone marrow involvement for documentation of disease staging. See Section 8.1 for response parameters.  
7.6.2.4 Basic immune reconstitution assay (i.e., CD4 and CD8 counts, and IgG
levels).  
7.6.2.5 Correlative studies: immune reconstitution, virologic, and specialized immunologic and DNA monitoring studies.  
7.6.2.6 Optional bone marrow biopsy and aspirate for participants without bone marrow involvement that consent to optional studies.  
7.6.2.7 Follow for survival if stop during 2-year post-treatment (Section 4.7)
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7.7 post-study follow-up

At the completion of all follow-up evaluations described in Section 7.5 or Section 7.6, the Off-Study Summary Form should be completed in AdvantageEDC. Follow for survival if stop during 2-year post-treatment (Section 4.7) Based on the FDA requirements for gene therapy protocols, for all participants on this study who received the gene-modified stem cells, whether they completed the study or came off the study early, all participants will be monitored for 15 years posttransplantation. The study team at each respective institution will make yearly phone calls to the participants' primary care physician, their oncologist, or their HIV physicians to fill out a simple questionnaire about participant health, HIV status, and development of any other cancer or clonal abnormality. For years 3-15, with participant consent, optional blood samples will be collected for HIV viral load, DNA, and immunological studies to monitor HIV and for research on vector parameters.
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8.0 measurement of effect 8.1

The Lugano Classification by Cheson DB, et al., 2014 (36) will be used for response assessments.  
- Time to Tumor Response (TTR): time from the first study treatment until documentation of first objective response.  
- Response Duration: time from first documentation of response to documentation of first relapse or progression.  
- Duration of CR: time from the first documentation of CR until first date that relapsed or progressive disease is objectively documented.
- Progression-Free Survival (PFS): time from start of study treatment to relapse, progression, or death from any cause, whichever occurs first. For this endpoint, persistent disease (not meeting criteria for progression) is not considered a failure. Participants who receive anti-cancer therapy other than the study drug (including consolidative radiation therapy or BMT) will be censored for all endpoints other than overall survival, including toxicity, response, and PFS.  
- Overall Survival (OS): time from start of study treatment to death.
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8.2 frequency of response evaluation

- Physical examination for any evidence of disease relapse should occur at the time of each history and physical exam.  
- In the absence of evident disease progression, response will be assessed formally at 3, 6, 12- and 24-months post-transplant per study calendar.  
- F-FDG-PET/CT or CT scan is required for restaging of lymphoma. - one marrow biopsy and aspirate with flow cytometry are required at 3 and 12-months post-transplant for all participants with bone marrow involvement at baseline. Additional bone marrow biopsy maybe required based on the discretion of participants' physicians.
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8.3 safety measures

All AEs will be monitored by ongoing review of reported adverse events by the protocol chair and the AMC Operations and Data Management Center, and will be discussed during the monthly investigators' Lymphoma Working Group conference calls (see Section 9.3 for rules for early study termination).
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9.0 statistical considerations 9.1 study

Each cohort will enroll 3 participants but can be extended to 6 participants if recommended by DSMB (this will occur only if there is a treatment failure either from failure to engraft or from Grade 3 or 4 toxicities, excluding alopecia).
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the primary endpoint of the

- Safety defined as timely engraftment (the collective establishment of a persistent absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 20,000 cells/mm3 for 3 consecutive days) at one-month post-transplant, in the absence of any study candidate-specific grade 3 and 4 non-hematopoietic organ toxicity, excluding alopecia, or any clonal expansion.
summary of changes
the major secondary endpoints of

- The efficacy of the candidate product, defined as establishment of > 5% mononuclear blood cells expressing anti-HIV genes in the peripheral blood at 3 months posttransplant.
The 5% threshold of the study has been set by our external advisory committee based on the outcome of previously performed clinical trials with similar vectors. However, we expect to have much higher levels of engraftment of our product based on high vector titer levels, new selection method for harvesting only transduced stem cells, improved and novel method of transduction, and the new sequence of transduction followed by freezing that has provided a significant improvement in our transduction efficiency.  
- To determine the presence, quantity, and duration of gene modified HIV-1 resistant peripheral blood cells and gut mucosal immune cells; and
- To study the integration sites of vector sequences in circulating cells.
In addition, the following minor endpoints will be studied as secondary endpoints:
- Progression-free survival  
- Overall survival
- Complete response rate and duration  
- Partial response rate and duration
- Time to neutrophil engraftment (first measurement of 3 consecutive laboratory values obtained on different days) of ANC > /= 500 cells/mm3)  
- Time to platelet engraftment (first measurement of 3 consecutive laboratory values on obtained different days) of platelets > /= 20,000 cells/mm3 without platelet transfusions 7 days prior)
- Hematologic function at Day 100 (ANC > 1500, Hb > 10g/dl without transfusion, and platelets > 100,000.  
- CD4 recovery at the conclusion of the study
AMC-097 (Version 9.0) 07FEB2022 85 NCI Version Date *07FEB2022* CLIENT CONFIDENTIAL
- Safety in terms of toxicities, infections, transfusions, and infusion-related reactions  
- HIV-1 viral load over time
- Persistence of vector-transduced cells over time The **exploratory endpoint** of this proposal is to evaluate the presence and the magnitude of expansion of HIV-1 resistant immune cells in the peripheral blood and gut mucosa of transplanted participants, subsequent to withholding ART.
summary of changes
9.2 sample size/accrual rate

A minimum of 2 and a maximum of 18 participants will be enrolled in the study, with more than 7 participants being enrolled only if one or more participants in a cohort experience failure of engraftment or Grade 3 or 4 toxicity, excluding alopecia. The accrual rate is anticipated to be 1 participant per month.  
With a sample size of 7, any toxicity occurring in as much as 20% of this patient population has a 79% chance of being seen in at least one of the participants in the study, and a toxicity occurring in as much as 10% of the population has a 52% chance of being observed in at least one participant. Toxicity will be summarized as the proportion experiencing a given toxicity or group of toxicities, at or above a specified level of severity, with exact 95% CIs. The analysis set for toxicity will be participants who enrolled and received at least one active treatment with gene therapy.
summary of changes
9.3 early stopping rules

The AMC DSMB is responsible for assessing trial data for dose escalation/cohort expansion and evaluating the stopping rules for this study. The composition and role of the AMC DSMB in this clinical trial is defined in the AMC DSMB charter. Based on pre-IND discussions with FDA, the following short term (day 30) and long term (day 90) stopping rules will be evaluated:
- Lack of timely hematopoietic engraftment in two out of 6 participants, within the first 30 days after stem cell infusion (as defined in Section 1.2). If this rule is met in cohort 3 (2.0 x 106 cells/µL), the DSMB will evaluate whether it is safe for the trial to proceed on cohort 3+ (3.0 x 106 cells/µL).  
- Grade 3/4 non-hematopoietic toxicity, excluding alopecia, directly associated with the gene therapy product in two out of 6 participants in each cohort within the first 90 days of the trial.  
- Death of one participant directly related to the gene therapy product (e.g., death due to lack of engraftment after day 20, but before day 30).
summary of changes
9.4 cohort escalation design

The dose escalation in this trial is based on the increasing ratio of the administrated transduced product to untransduced mobilized peripheral stem cells. Please see the clinical trial design section for the details of dose escalation in each cohort.
summary of changes
9.5 analysis of secondary endpoints

Secondary and exploratory endpoints will be summarized descriptively. Efficacy rates will be summarized by the proportion of participants who meet the criteria for efficacy (defined in Section 9.1), with 95% exact binomial confidence intervals (CIs). For dichotomous endpoints (e.g., the presence of gene modified HIV resistant peripheral blood cells and gut mucosal immune cells, complete response) the frequency, proportion, and exact 95% confidence interval for proportion will be calculated. Continuous measures (e.g., quantity and duration of gene modified HIV resistant peripheral blood cells and gut mucosal immune cells) will be summarized by mean (SD) and median (range), with log transformation if necessary, for skewed measures, as would be typical for cell counts. Time-to-event data (e.g., overall survival, progression free survival, duration of response) will be presented graphically by Kaplan-Meier plots and summarized by estimated median time to event (if that is estimable from the data) with 95% confidence interval. Separate inferences for the three cohorts will not be possible, given the limited sample size, but descriptive summaries will be prepared for key variables to inform decisions about the next stage of clinical trials.
summary of changes
9.6 amc policy for monitoring

This protocol will follow the AMC's policy for data monitoring (See Appendix VI), which serves to assure that:
- Only participants who meet the study eligibility criteria are enrolled.  
- The informed consent process is conducted appropriately.  
- Data is collected and analyzed as specified in the protocol.  
- Adverse events are reviewed promptly and reported as required.  
- Privacy and confidentiality of study participants are maintained.
summary of changes
independent data and safety monitoring

All gene therapy protocols according to NIH and FDA guidelines are included in the "high risk" category and therefore require a Data and Safety Monitoring Board (DSMB) for assessing the risk to the patient population. The AMC DSMB will be used as an independent group to monitor the potential efficacy and/or toxicities of the protocol. The members of the DSMB (at least 6 members) will be chosen with appropriate broad spectrum of expertise, including biostatisticians, HIV experts, gene therapy experts, bioethics experts, HIV patient advocates, and lay members. They will set the guideline to assess the study risk by description of anticipated adverse events, adverse event grading and plans for reporting adverse events. They will also institute a safety-monitoring plan The AMC DSMB will be given a report by the PI(s) indicating the number of participants who have enrolled, a list of all adverse events, and the results of clinical measures. The AMC DSMB will review the safety data for the participants in each cohort after the 30 days post-transplant follow up period to identify whether DLT occurred, and if a decision should be made to proceed with the study for the subsequent participants according to the DLT definition and dose escalation rules in Section 4.3. At the time of each review, the AMC DSMB will be asked to recommend continuation or discontinuation of the trial. If, in the opinion of the AMC DSMB there is any indication of compromise of the safety of the participants, the AMC DSMB will contact the PI(s) and the study will be halted.
summary of changes
10.0 role of data management

Access to the internet data entry system for this study, AdvantageEDCSM, and instructions for recording of study data on CRFs will be provided by the AMC ODMC at www.amcoperations.com. Participating institutions are responsible for submitting data and/or data forms via AdvantageEDCSM in accordance with the AMC Data Entry Guide and specific form instructions and in compliance with 21 CFR 11, within the timelines specified by the AMC's Standards of Procedure for Site Performance Measures.
summary of changes
10.2 data quality

It is the responsibility of the AMC ODMC to assure the quality of data for the study (See Appendix VI, AMC Data and Safety Monitoring Plan). This role extends from protocol development to generation of the final study database.
summary of changes
10.3 data monitoring

This study will be monitored in compliance with AMC policies and by the Clinical Data Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific CDUS data will be submitted electronically to CTEP on a quarterly basis. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review.
summary of changes
11.0 ethical and regulatory considerations

The principles of Institutional Review Board (IRB) approval and informed consent described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 56) and Department of Health and Human Services (DHHS) regulations for the Protection of Human Subjects regulations (45 CFR Part 46), as well as the International Conference on Harmonization guideline for Good Clinical Practice E6 (R1) and Declaration of Helsinki must be followed. IRB approval of the protocol and the informed consent form must be given in writing. The sponsor's designee (AMC ODMC) must receive a copy of the letter of approval from the IRB, which specifically approves the protocol and informed consent, before participant enrollment. The IRB must also approve any significant changes to the protocol and documentation of this approval must be sent to the AMC ODMC. The IRB must review the research project at least once every 365 days during the duration of the project. Continuing approval of the project must also be given in writing and provided to the AMC ODMC. Records of all study review and approval documents must be kept on file by the Investigator and are participant to inspection during or after completion of the study. AEs must be reported to the IRB according to local procedures. The IRB should receive notification of completion of the study and final report within 3 months of study completion and termination. The Investigator will maintain an accurate and complete record of all submissions made to the IRB, including a list of all reports and documents submitted. Written informed consent will be obtained from the participant. The nature and significance of the risks associated with the study must be explained to the participant. The informed consent will describe the purpose of the study, the procedures to be followed, the risks and benefits of participation, all risks of the investigational agent(s) and/or study participation as listed in the model informed consent form, and all other elements of informed consent as required by regulation. A copy of the consent form will be given to the participant to keep. In addition, any institution(s) conducting research according to the guidelines of this protocol is required to adhere to local and national laws and regulations governing the confidentiality and disclosure of health information.
summary of changes
11.2 multi-site research

- All sites have the most current version of the protocol, consent document, and HIPAA
authorization.  
- All required approvals will be obtained at each site (including approval by the site's IRB of record and Institutional Biosafety Committee as applicable).  
- All modifications will be approved by FDA first and they will be communicated to sites and approved (including approval by the site's IRB of record) before the modification is implemented.  
- All engaged participating sites will safeguard data as required by local information security policies.  
- All local site investigators conduct the study appropriately.  
- All non-compliance with the study protocol or applicable requirements will be reported in accordance with local policy.  
The DSMB will communicate the information below to all the engaged participating sites:
- Problems.  
- Interim results.  
- The closure of a study.
summary of changes
11.3 data management and confidentiality

Prior to study enrollment, participants will be contacted by a member of the research team in a private setting such as the clinic exam room. The research team will explain the study treatment, procedures, and the timing of each to the participants. The participants will be offered the opportunity to ask questions. After study enrollment, participants' privacy interests will be respected at all times, and requests for specific privacy requirements will be met if at all possible, taking into consideration the study protocol requirements and the participants' welfare.
summary of changes
hipaa

A HIPAA authorization will be obtained for every participant (or Legally Authorized Representative, if applicable) enrolled to the study, and it will be done at the time the participant is consented to the study. The HIPAA Authorization approved by the UC Davis Compliance Office or the participating site's compliance office will be used.  
After a study participant has signed a study-specific HIPAA authorization and an IRBapproved study consent form, the research team is permitted to access all sources of their medical information and protected health information (PHI). This includes the participant's electronic medical record (EMR) as well as any scans or medical/PHI documentation in paper form.
summary of changes
privacy risks

The Sponsor-Investigator will maintain all study records according to ICH-GCP and applicable regulatory requirement(s). Data and/or specimens will be labeled with a code that the research team can link to personal identifying information when acquired. The code sheet will be secured and kept separate from the dataset. The researchers will store study records and other information in a secure location and will grant access only to those with a need to know. However, just like with other personal information kept by health care providers, banks, and others, even these safeguards cannot guarantee absolute protection of the data. If private information gets into the wrong hands, it can cause harm. Although rare, there are reported cases of breaches that have resulted in discrimination in insurance or employment.
summary of changes
11.4 changes to the protocol

Any change or addition to this protocol requires a written protocol amendment that must be approved by CTEP and the Investigator before implementation. All amendments require approval by the IRB of the treating institution. A copy of the written approval of the IRB must be sent to the ODMC.
summary of changes
11.5 vulnerable populations

This study is not designed to enroll any participants from the following vulnerable populations: pregnant women, neonates, prisoners, persons who have not attained the legal age for consent to treatments or procedures involved in the research, or cognitively impaired adults.
summary of changes
11.6 non-english-speaking participants

Non-English-speaking participants are not excluded from participation in this trial. For potential participants who do not speak English, local IRB policy for translation of informed consent forms and/or documentation of a short form consent must be followed.
summary of changes
11.7 women and minorities

This study is being conducted by the NCI-sponsored AIDS Malignancy Consortium (AMC). As part of their contractual obligations, each participating site within the AMC and the AMC as a whole is required to assure that the participation of women and minority participants reflects the percentage representation of these populations in their geographic region and, for the AMC, the United States as a whole. As such, it is expected that the representation of participants on this trial will reflect the constitution of the respective populations.  
| Table 11-A: Accrual Targets                       | Sex/Gender                               |       |       |    |    |
|---------------------------------------------------|------------------------------------------|-------|-------|----|----|
| Ethnic Category                                   | Females                                  | Males | Total |    |    |
| Hispanic or Latino                                | 1                                        | +     | 3     | =  | 4  |
| Not Hispanic or Latino                            | 1                                        | +     | 13    | =  | 14 |
| Ethnic Category: Total of all participants        | 2                                        | +     | 16    | =  | 18 |
| Racial Category American Indian or Alaskan Native | 0                                        | +     | 0     | =  | 0  |
| Asian                                             | 0                                        | +     | 1     | =  | 1  |
| Black or African American                         | 1                                        | +     | 3     | =  | 4  |
| Native Hawaiian or other Pacific Islander         | 0                                        | +     | 1     | =  | 1  |
| White                                             | 1                                        | +     | 11    | =  | 12 |
| Racial Category: Total of all participants        | 2                                        | +     | 16    | =  | 18 |
| 11.8                                              | Compensation for Research-Related Injury |       |       |    |    |  
Participants are instructed that it is important they promptly tell the person in charge if they believe that they have been injured because of taking part in this study. For participants who are injured as a result of being in this study, individual institutions will provide necessary medical treatment based on their own policies. Depending on the circumstances, the costs of the treatment may be covered by the University or the study sponsor or may be billed to the participant's insurance company just like other medical costs. The University and the study sponsor do not normally provide any other form of compensation for injury.
summary of changes
11.9 economic burden to participants

Standard of care and other routine costs involved with this study will be billed to the participant or the participant's insurance carrier, Medicare, or Medi-Cal, where appropriate. These costs are consistent with the routine care participants would receive outside of the study and may include standard medical tests and examinations (such as blood work and physical exams, pharmacy charges, scans, etc.). Whenever possible, preauthorization will be obtained. If the costs are not covered, these costs will be discussed with the participant prior to proceeding with the study. The participant will be responsible for any costs not covered by his/her insurance.
summary of changes
12.0 references

1. Martinez‐Picado J, et al., 2000. Antiretroviral resistance during successful therapy of HIV‐1 type 1 infection. Proc Natl Acad Sci USA; 97:10948–10953.  
2. Winters MA, et al., 2000. Frequency of antiretroviral drug resistance mutations in HIV-1 strains from patients failing triple drug regimens. The Terry Beirn Community Programs for Clinical Research on AIDS. Antivir Ther; 5:57–63.  
3. Bacheler LT, et al., 2000. Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrob Agents Chemother; 44:2475–2484.  
4. Lafeuillade A, et al., 2001. Phenotypic and genotypic resistance to nucleoside reverse transcriptase inhibitors in HIV-1 clinical isolates. HIV-1 Med; 2:231-235.  
5. Henrich TJ, et al., 2010. Evolution of CCR5 antagonist resistance in an HIV-1 subtype C
clinical isolate. J Acquir Immune Defic Syndr. 55:420-427.  
6. Tilton JC, et al., 2010. A maraviroc resistant HIV-1 with narrow cross-resistance to other CCR5 antagonists depends on both N-terminal and extracellular loop domains of drugbound CCR5. J Virol. 84:10863-10876.  
7. Aiuti F and Mezzaroma I., 2006. Failure to reconstitute CD4+ T cells despite suppression of HIV-1 replication under HAART. AIDS Rev. 8:88-97.  
8. Ianello A, et al., 2010. Potential role of IL-18 in the immunopathogenesis of AIDS, HIV-1associated lipodystrophy and related clinical conditions. Curr HIV-1 Res. 8:147-164.  
9. Baldanti F, et al., 2010. Early emergence of raltegravir resistance mutations in patients receiving HAART salvage regimens. J Med Virol. 82:116-122.  
10. Mascolini M, et al., 2008. Clinical implications of resistance to antiretrovirals: new resistance technologies and interpretations. Antivir Ther. 13:319-34.  
11. Strayer DS, et al., 2005. Current Status of Gene Therapy Strategies to Treat HIV- 1/AIDS.  
Mol. Ther. 11:823-841.  
12. Humeau LM, et al., 2004. Efficient lentiviral vector-mediated control of HIV-1 replication in CD4 lymphocytes from diverse HIV-1+ infected patients grouped according to CD4 count and viral load. Mol. Ther. 9:902-913.  
13. Mitsuyasu RT, et al., 2009. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med. 15:285-292.  
14. DiGiusto DL, et al., 2010. RNA-based gene therapy for HIV-1 with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS- related lymphoma. Sci Transl Med. 2:36ra43.  
15. Kimpel, J., Braun, S.E., Qiu, G., Wong, F.E., Conolle, M., Schmitz, J.E., Brendel, C., Humeau, L.M., Dropulic, B., Rossi, J.J. et al., 2010. Survival of the fittest: positive selection of CD4+ T cells expressing a membrane-bound fusion inhibitor following HIV-1 infection. PLoS One, 5, e12357.  
16. Van Lunzen, et al., 2007. Transfer of autologous gene-modified T cells in HIV-1- infected patients with advanced immunodeficiency and drug-resistant virus. Mol Ther 15: 10241033.  
17. Von Laer, D, Hasselmann, S, Hasselmann, K, 2006. Gene therapy for HIV-1 infection: what does it need to make it work? J Gene Med 8: 658-667.  
18. Podsakoff GM, Engel BC, Carbonaro DA, Choi C, Smogorzewska EM, Bauer G, Selander D,
Csik S, Wilson K, Betts MR, Koup RA, Nabel GJ, Bishop K, King S, Schmidt M, von Kalle C, Church JA, Kohn DB., 2005. Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti- HIV gene to bone marrow CD34(+) cells. Mol Ther. 2005 12:77-86.  
19. Aviran, S., Shah, P.S., Schaffer, D.V. and Arkin, A.P., 2010. Computational models of HIV-1 resistance to gene therapy elucidate therapy design principles. PLoS Comput. Biol., 6, e1000883.  
20. Applegate, T.L., Birkett, D.J., McIntyre, G.J., Jaramillo, A.B., Symonds, G. and Murray, J.M.,
2010. In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy. Retrovirology, 7, 83.  
21. Kessinger A, Nademanee A, Forman SJ, Armitage JO., 1990. Autologous bone marrow Transplantation for Hodgkin's and non-Hodgkin's lymphoma. Hematol Oncol Clin North Am. 1990; 4:577.  
22. Philip T, Guglielmi C, Hagenbeek A, Somers R, van der Lelie H, Bron D, Sonnefeld P,
Gisselbrecht C, Cahn J-Y, Harousseau J-L, Coiffier B, Biron P, Mandelli F, Chauvin F., 1995. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy sensitive non-Hodgkin's lymphoma. N Engl J Med 1995;333:1540.  
23. Vose JM, Anderson JR, Kessinger A, Bierman Ph, Coccia P, Reed EC, Gordon B, Armitage JO., 1993. High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 1993;11:1846.  
24. Krishnan A, Molina A, Zaia, J, et al., 2005. Durable remission with autologous stem cell transplantation for high-risk HIV-1-associated lymphomas. Blood. 2005;105:874.  
25. Spitzer TR, Ambinder RF, Lee JY, et al., 2008. Dose-reduced busulfan, cyclophosphamide and autologous stem cell transplantation for human immunodeficiency virus-associated lymphoma: AIDS Malignancy Consortium study. Biol Blood Marrow Transplant. 2008;14:59.  
26. Gabarre J, LeBlond V, Sutton L, et al., 1996. Autologous bone marrow transplant in relapsed HIV-1-related non-Hodgkin's lymphoma. Bone Marrow Transplant. 1996;18:1195.  
27. Re A, Cattaneo C, Michieli M, et al., 2003. High-dose therapy and autologous peripheral blood stem-cell transplantation as salvage treatment for HIV-1-associated lymphoma in patients receiving highly active antiretroviral therapy. J Clin Oncol. 2003;23:4423.  
28. Serrano D, Carrion R, Balsolobre P, et al., 2005. HIV-1-associated lymphoma successfully treated with peripheral blood stem cell transplantation. Exp Hematol. 2005;33:487.  
29. Balsalobre P, Diez-Martin JL, Re A et al., 2009. Autologous stem-cell transplantation in patients with HIV-1-related lymphoma. J Clin Oncol. 2009: 27:2192.  
30. Diez-Martin JL, Balsalobre P, Re A, et al., 2009. Comparable survival between HIV-1+ and HIV-1- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation. Blood 2009: 113:6011.  
31. Lundgren JD, Babiker A, El-Sadr W, et al., 2008. An inferior clinical outcome of the CD4+
cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ cell counts and HIV-1 RNA levels during follow-up. J Infect Dis 2008; 197: 114555.  
32. Pai NP, Tulsky JP, Lawrence J, et al., Structured treatment interruptions (STI) in chronic suppressed HIV-1 infection in adults (review). Cochrane Library 2008; 1:1-37.  
33. G. Carcelain et al., 2001. Transient mobilization of human immunodeficiency virus (HIV-1)-
specific CD4 T helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV-1 type 1 infection. J. Virol., 75, 2001; 234–241 34. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-1-infected adults and adolescents. Department of Health and Human Services. 08 April 2015; 1-288. Available at, http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf 35. Alvarnas J, Le Rademacher J, et al., 2014. Autologous Hematopoietic Stem Cell Transplant
(AHCT) in Patients with Chemotherapy-Sensitive, Relapsed/Refractor (CSRR) Human Immunodeficiency Virus (HIV)-Associated Lymphoma (HAL): Results from the Blood and marrow Transplant Clinical Trials network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial. ASH Oral and Poster Abstract 674, 08 December 2014; Available at, https://ash.confex.com/ash/2014/webprogram/Paper70947.html 36. Cheson DB, Fisher RI, et. al, 2014. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014; 32(27): 3059-68.
appendix i schedule of evaluations
12.0 references

| App - 1A: Pre-Transplant Screening; Mobilization Period                                                                                                                                                                                              | Within 1  Week Prior  to  Admission  for  Transplant   |    |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------|----|----|
| Within 8                                                                                                                                                                                                                                             |                                                        |    |    |
| Weeks Prior  to Enrollment  (Stem Cell  Collection)                                                                                                                                                                                                  | On the Day of  Admission for                           |    |    |
| Transplant Before  Start of  Chemotherapy                                                                                                                                                                                                            |                                                        |    |    |
| Required Studies/Testing                                                                                                                                                                                                                             |                                                        |    |    |
| History & Physical with assessment of physical staging of the  disease, Height and Weight, BSA, neurologic examination,  review of current and prior anti-retroviral regimens, concomitant  medications, and history of any AIDS defining conditions | X                                                      | X  | X  |
| Hepatitis Panel5 (HAV Ab, HBsAg, HBcAb HBsAb, Hepatitis C  Ab), HSV 1 & 2 IgG and PCR, Toxoplasma IgG, VZV IgG,                                                                                                                                      | X                                                      |    |    |
| Syphilis (RPR or VDRL), HIV-1 and HTLV antibody CXR                                                                                                                                                                                                  | X                                                      | X  |    |
| EKG                                                                                                                                                                                                                                                  | X                                                      |    |    |
| PFTs; DLCO, FEVI, FVC4]                                                                                                                                                                                                                              | X                                                      |    |    |
| Creatinine Clearance5                                                                                                                                                                                                                                | X                                                      |    |    |
| CMV Immunoglobulin level and CMV quantitative PCR                                                                                                                                                                                                    | X                                                      |    |    |
| Bone marrow biopsy and aspirate with flow cytometry for  pathology                                                                                                                                                                                   | X                                                      |    |    |
| HIV-1 RNA10 , CD4 Count                                                                                                                                                                                                                              | X                                                      | X  |    |
| HepB DNA PCR and HepC DNA PCR1                                                                                                                                                                                                                       | X                                                      |    |    |
| Cardiac Ejection Fraction (by 2D ECHO or MUGA scan)4                                                                                                                                                                                                 | X                                                      |    |    |
| B –HCG Test for Females of Childbearing Potential                                                                                                                                                                                                    | X                                                      | X  |    |
| Quantitative immunoglobulins (IgM, IgG, and IgA)                                                                                                                                                                                                     | X                                                      |    |    |
| Staging CT or PET CT                                                                                                                                                                                                                                 | X                                                      |    |    |
| Karnofsky Performance Score/ECOG Performance Status                                                                                                                                                                                                  | X                                                      | X  |    |
| CBC with differential, Platelet Count, CMP, LDH and Uric acid                                                                                                                                                                                        | X                                                      | X  |    |
| CCR5-tropism assay2                                                                                                                                                                                                                                  | X                                                      |    |    |
| Immune reconstitution assays, basic3                                                                                                                                                                                                                 | X                                                      |    |    |  
The schedule of evaluations below applies to all participants on study.  
| Within 1  Week Prior  to  Admission  for  Transplant                                                                                                                                                                                |                              |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| Within 8                                                                                                                                                                                                                            |                              |
| Weeks Prior  to Enrollment  (Stem Cell  Collection)                                                                                                                                                                                 | On the Day of  Admission for |
| Transplant Before  Start of  Chemotherapy                                                                                                                                                                                           |                              |
| Required Studies/Testing                                                                                                                                                                                                            |                              |
| PT/PTT assessment5                                                                                                                                                                                                                  | X                            |
| Immunology assays, correlatives8                                                                                                                                                                                                    | X                            |
| DNA monitoring assays, correlatives9                                                                                                                                                                                                | X                            |
| Virology assays, correlatives8                                                                                                                                                                                                      | X                            |
| Banking of CD34+ depleted PBMC from apheresis samples6                                                                                                                                                                              | X                            |
| Optional donation to the ACSR7                                                                                                                                                                                                      | X                            |
| 1- Only if the core Ab is positive for HepB or the HepC Ab is positive, respectively. 2- We will use both commercially available assays (i.e., phenotypic assay performed by Monogram Biosciences and the genotypic assay performed |                              |  
2- We will use both commercially available assays (i.e., phenotypic assay performed by Monogram Biosciences and the genotypic assay performed by Quest Diagnostics) (See Appendix IX).  
3- CD4, CD8, and IgG will be collected at the participating site as standard of care.  
4- To be collected within 4 weeks prior to study enrollment. 5- To be collected within 3 weeks prior to study enrollment.  
6– CD34+ depleted cells obtained from GMP Facility.  
7– See Appendix IV for ACSR Informed Consent and Appendix III for ACSR Specimen Preparation and Shipping Instructions. 8- On all visits where immunological and viral correlatives are to be completed, 40 mL of blood (total) will be drawn in lavender top (EDTA) tubes and 5 mL of blood will be drawn in red top tubes.  
9- On all visits where DNA monitoring correlatives are to be completed, 20 mL of blood will be drawn in lavender top (EDTA) tubes. 10- Within 6 months before study enrollment. See Section 3.1.2.2.  
| App - 1B: Post-Transplant Follow Up                                                                                                                     | Discontinuation   | Years Post-HCT6   |    |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|-------------------|----|----|----|----|-----|----|----|----|----|-----|----|----|----|----|----|----|------------------------------------|---------------|
| Early Disc., and OffStudy                                                                                                                                                         |                   |                   |    |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| Weeks Post-HCT                                                                                                                                          | Months Post-HCT   |                   |    |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| Study Assessments/Testing Post  Transplant                                                                                                              | 1                 | 2                 | 3  | 4  | 6  | 2  | 3   | 4  | 6  | 8  | 10 | 12  | 14 | 16 | 18 | 20 | 22 | 24 | Within 30 days of  discontinuation | 3-15, once/yr |
| History & Physical, including  performance status, height, weight and  BSA, neurological exam, concomitant  medication review, and Toxicity  Assessment | X                 | X                 | X  | X  | X  | X  | X   | X  | X  | X  | X  | X   | X  | X  | X  | X  | X  | X  | X                                  |               |
| Assessment of engraftment                                                                                                                               | X                 | X                 | X  | X  | X  | X4 |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| CBC, LDH, Uric Acid, CMP                                                                                                                                | X                 | X                 | X  | X  | X  | X  | X   | X  | X  | X  | X  | X   | X  | X  | X  | X  | X  | X  | X                                  |               |
| CT or PET-CT restaging                                                                                                                                  | X                 | X                 | X  | X  | X  |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| Required bone marrow biopsy and  aspirate with flow cytometry (for  restaging), if bone marrow involvement  at baseline2                                | X                 | X                 | X  |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| Optional bone marrow biopsy and  aspirate with flow cytometry (for  research) for those without bone marrow  involvement at baseline2                   | X                 | X                 | X  |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| GI biopsy                                                                                                                                               | X5                | X5                |    |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| Immune Reconstitution Assays, basic1                                                                                                                    | X                 | X                 | X  | X  | X  | X  | X   | X  | X  | X  | X  | X10 |    |    |    |    |    |    |                                    |               |
| Immune Reconstitution Assays,  correlative studies                                                                                                      | X                 | X                 | X  | X  | X  |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| CMV PCR                                                                                                                                                 | X                 | X                 | X  | X  | X  | X  | X   |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| HIV-1 viral load                                                                                                                                        | X                 | X                 | X  | X  | X  | X  | X   | X  | X  | X  | X  | X10 |    |    |    |    |    |    |                                    |               |
| Virologic and specialized immunologic  assays, correlative studies3,8                                                                                   | X                 | X7                | X  | X  | X  | X  | X10 |    |    |    |    |     |    |    |    |    |    |    |                                    |               |
| DNA monitoring, correlative studies4,9                                                                                                                  | X                 | X                 | X  | X  | X  | X  | X   | X  | X  | X  | X  | X10 |    |    |    |    |    |    |                                    |               |
| AMC 097 (Version 9.0) 07FEB2022                                                                                                                         | 99                |                   |    |    |    |    |     |    |    |    |    |     |    |    |    |    |    |    |                                    |               |  
AMC 097 (Version 9.0) 07FEB2022 99  
NCI Version Date 07FEB2022  
CLIENT CONFIDENTIAL  
| Discontinuation                                                               | Years Post-HCT6                                                                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |                                    |               |
|-------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|----|------------------------------------|---------------|
| Early Disc., and OffStudy                                                                               |                                                                                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |                                    |               |
| Weeks Post-HCT                                                                | Months Post-HCT                                                                                                                                                                                                   |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |                                    |               |
| Study Assessments/Testing Post  Transplant                                    | 1                                                                                                                                                                                                                 | 2  | 3  | 4  | 6  | 2  | 3  | 4  | 6  | 8  | 10 | 12 | 14 | 16 | 18 | 20 | 22 | 24 | Within 30 days of  discontinuation | 3-15, once/yr |
| Adverse event assessment                                                      | X                                                                                                                                                                                                                 | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |                                    |               |
| Telephone follow-up for HIV status and  development of secondary malignancies | X                                                                                                                                                                                                                 | X6 |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |                                    |               |
| 1.                                                                            | At these time points basic immunological tests (i.e., CD4, CD8, and IgG will be done). If collection timepoints overlap with collections as part of ATI / ART resumption, then labs will not need to be repeated. |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |    |                                    |               |  
2. Bone marrow biopsy and aspirate with flow cytometry will be performed as a part of restaging for participants with bone marrow involvement by the lymphoma. Optional bone marrow biopsy and aspirate with flow cytometry will be performed for participants without bone marrow involvement that consent to optional studies.  
3. Samples will be collected and stored for possible HIV-1 nucleotide sequence analyses for ART drug resistance; Samples will also be collected and stored to explore the impact of anti-HIV transduced stem cells on genetic makeup of HIV-1 populations (e.g., co-receptor usage, genetic changes in tat or TRIM5α targets). If needed, we will use both commercially available assays (i.e., phenotypic assay performed by Monogram Biosciences and the genotypic assay performed by Quest Diagnostics).  
4. Assessment for hematological engraftment will stop at 2 months. However, assessment of anti-HIV-1 transduced clonal cell expansion will continue as a part of correlative studies for the entire period of follow up.  
5. GI biopsies (upper endoscopy) will be offered to all the participants of the study as a voluntary option at 6 months post-transplant (or when CD4 count reaches above 300 cell/mm3) and will be repeated in two months after the first GI biopsy.
6. The follow-up in years 3-15 will be performed by phone calls to participants or their health care provider. The telephone contact for follow-up is not required for participants who discontinue protocol treatment early for any reason (early discontinuation) but is required for participants who complete all treatment per-protocol.  
7. To be collected at 10 weeks post-transplant.  
8. On all visits where immunological and viral correlatives are to be completed, 40 mL of blood (total) will be drawn in lavender top (EDTA) tubes and 5 mL of blood will be drawn in red top tubes for immunological studies and 40 mL of blood (total) will be drawn in lavender top (ETA) tubes for viral studies.  
9. On all visits where DNA monitoring correlatives are to be completed, 20 mL of blood will be drawn in lavender top (EDTA) tubes.  
10. Participants that consent to optional studies will have blood samples (30 mL) collected to monitor the participant's HIV and vector parameters.
appendix i schedule of evaluations
app - 1c analytic treatment

The schedule during the ATI period will be defined by clinical course and the characteristics of any virus rebound. ART will be initiated for clinical events, sustained drop in CD4+T cell counts or sustained increased in viremia as described in Section 2.4.1. Prior to these events, participants will be followed. If required clinical and laboratory assessments (physical exam, medical history and medical review, toxicity assessments, CD4/CD8 counts and HIV VL) during ART withdrawal overlap with required post-treatment follow-up evaluations then these assessments do not need to be repeated. Clinical assessments, and ATI counseling may be performed remotely to minimize in-person visits during the ATI.  
| Post ATI1                           |                 |            |              |    |     |    |
|-------------------------------------|-----------------|------------|--------------|----|-----|----|
| Assessments                         | Within One Week | Weeks 1-12 | Extended ATI |    |     |    |
| Prior to ATI                        | (Weeks 13+)     |            |              |    |     |    |
| Weekly                              | Weekly          | ART        | W4           | W8 | W24 |    |
| Resumption                          |                 |            |              |    |     |    |
| COVID Testing2                      | X               |            |              |    |     |    |
| ATI                                 | X               | X          |              |    |     |    |
| Clinical Assessments3               | X               | X          | X            | X  | X   | X  |
| T cell counts (CD4 and CD8)         | X               | X          | X            | X  | X   | X  |
| HIV Viral Load4                     | X               | X          | X            | X  | X   | X  |
| Plasma and PBMCs5                   | X               | X          | X            | X  |     |    |
| Pre-ATI                             | counseling      | and        | X            |    |     |    |
| disclosure6 Ongoing ATI counseling6 | X               | X          |              |    |     |    |  
1. Once ART is restarted, participants will be followed at the time of ART restart, and at 4, 8, and 24 weeks after restart. 5. Plasma and PBMCs will be collected in four (4) 10 mL EDTA tubes and cryopreserved at the time of ART resumption and at Weeks 4, 8 and 24 on ART. 6. Participants must be provided the participant HIV interruption participation disclosure sheet (Appendix XII) and have pre-ATI counseling performed (Appendix XI) prior to ATI. ATI risk mitigation counseling must be performed weekly during ATI.  
| Correlative                                   | 2         |        |       |        |        |        |        |        |        |        |    |                     |
|-----------------------------------------------|-----------|--------|-------|--------|--------|--------|--------|--------|--------|--------|----|---------------------|
| Laboratory                                    | Baseline  | 4      | 2     | 10     | 3      | 4      | 6      | 8      | 10     | 12     | 18 | Discont.n Follow-up |
| Months                                        | Years 3-5 |        |       |        |        |        |        |        |        |        |    |                     |
| 24                                            |           |        |       |        |        |        |        |        |        |        |    |                     |
| Weeks                                         | Weeks     | Months | Weeks | Months | Months | Months | Months | Months | Months | Months |    |                     |
| Immunology (Pollard  Lab) DNA (Anders on Lab) |           |        |       |        |        |        |        |        |        |        |    |                     |
| Virology                                      |           |        |       |        |        |        |        |        |        |        |    |                     |
| (Henrich  Lab)                                |           |        |       |        |        |        |        |        |        |        |    |                     |
| Optional  GI                                  | X         | X      |       |        |        |        |        |        |        |        |    |                     |
| Biopsy1, 2  (Pollard Lab)                     |           |        |       |        |        |        |        |        |        |        |    |                     |  
| CCR5- Tropism  assays                                    |
|----------------------------------------------------------|
| (Monogram  Bioscience) Optional  Bone  Marrow  Biopsies3 |  
1 Participants must sign the separate consent form to participate in these optional studies 2 If the participant's CD4 count is not >300 cells/mm3 at the 6-month timepoint, GI biopsies may be delayed until the participant's CD4 count has reached 300 cells/mm3, and biopsies will be repeated 2 months after the first collection. 3 For participants with bone marrow involvement at baseline that consent to optional collections.  
| KEY:  5mL redtop tube       | 4mL purple top (EDTA) tube   |
|-----------------------------|------------------------------|
| 10mL purple top (EDTA) tube |                              |  
| APPENDIX II: PERFORMANCE STATUS SCALES   |                                                                                                      |       |                                                                                                                                   |
|------------------------------------------|------------------------------------------------------------------------------------------------------|-------|-----------------------------------------------------------------------------------------------------------------------------------|
| Karnofsky Performance Scale              | ECOG Performance Status Scale                                                                        |       |                                                                                                                                   |
| Percent                                  | Description                                                                                          | Grade | Description                                                                                                                       |
| 100                                      | Normal, no complaints, no                                                                            | 0     | Normal activity. Fully active, able to                                                                                            |
| evidence of disease.                     | carry on all pre-disease performance  without restriction.                                           |       |                                                                                                                                   |
| Able to carry on normal activity;        |                                                                                                      |       |                                                                                                                                   |
| 90                                       | minor signs or symptoms of  disease.                                                                 | 1     | Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able to  carry out work of a light or |
| Cares for self, unable to carry on       | sedentary nature (e.g., light                                                                        |       |                                                                                                                                   |
| 70                                       | housework, office work).                                                                             |       |                                                                                                                                   |
| normal activity or to do active  work.   |                                                                                                      |       |                                                                                                                                   |
| 80                                       | Normal activity with effort; some  signs or symptoms of disease.  Requires occasional assistance but |       |                                                                                                                                   |
| 60                                       | is able to care for most of his/her  needs.                                                          | 2     | In bed <50% of the time.  Ambulatory and capable of all selfcare, but unable to carry out any  work activities. Up and about more  than 50% of waking hours.                                                                                                                                   |
| 50                                       | Requires considerable assistance  and frequent medical care.                                         |       |                                                                                                                                   |
| 40                                       | Disabled, requires special care and                                                                  | 3     | In bed >50% of the time. Capable of                                                                                               |
| assistance.                              | only limited self-care, confined to  bed or chair more than 50% of  waking hours.                    |       |                                                                                                                                   |
| 30                                       | Severely disabled, hospitalization  indicated. Death not imminent.                                   |       |                                                                                                                                   |
| 20                                       | Very sick, hospitalization                                                                           | 4     | 100% bedridden. Completely                                                                                                        |
| indicated. Death not imminent.           | disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                      |       |                                                                                                                                   |
| 10                                       | Moribund, fatal processes  progressing rapidly.                                                      |       |                                                                                                                                   |
| 0                                        | Dead.                                                                                                | 5     | Dead.                                                                                                                             |
appendix i schedule of evaluations
appendix iii aids and cancer

To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc.  
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These shippers may be ordered at the SAF-T-PAK website: www.saftpak.com. The following instructions below are for use with the recommended STP-210 shipper. If using another federally approved diagnostic shipper, please follow instructions provided for that specific shipper.  
NOTE: Specimens MUST BE SHIPPED **Mondays** through **Wednesday** as an OVERNIGHT PRIORITY shipment. Specimens are NOT ACCEPTED ON FRIDAYS
OR SATURDAYS in the ACSR.
appendix i schedule of evaluations
b. specimen preparation packaging and

Draw two 8.5 cc (mL) yellow top [acid citrate dextrose (ACD)] tubes from study participant. With a black, water resistant, sharpie pen, label each specimen with the following information:
- AMC Protocol \# 097  
- AMC Participant ID\#
- Date and time of collection
- Specimen type, (i.e., WB=Whole Blood, P=Plasma, S=Serum, or Tissue)  
- Specimen purpose: Donation
Specimen shipment
- Seal the tops of the two 8.5 cc yellow tops with parafilm.  
- Place the two sealed tubes into bubble wrap (provided in STP-210 kit).  
- Tape around the bubble wrap so that the roll stays together and the tubes cannot fall out or break.  
- Place absorbent material sheet around the bubble wrapped tubes and slip into a biohazard poly-bag and "self-seal."
- Place poly-bag containing tubes into the white TYVEK bag and seal.  
- Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the cardboard shipper with clear packing/shipping tape.  
- Affix the FedEx airbill on blank side of the shipper making sure that it is marked
"FedEx PRIORITY OVERNIGHT."
- Mark "OTHER" in the airbill under "Packaging." Please use the FedEx \# available on the AMC member's only website.  
- Under airbill section "Special Handling" indicate, "YES-SHIPPERS DECLARATION
NOT REQUIRED."
- Place "From/To" information onto areas provided on the shipper.  
- Make certain that shipper is already either pre-labeled with 'UN\#3373' stamp or make a paper label with 'UN\#3373" and affix it to the shipper.  
- Make certain that the net volume of the specimen being shipped is written in the space provided on the shipper or make a separate label with the volume in mL and affix to the shipper.  
- Affix airbill to shipper so that the 'UN' and 'VOLUME' labels are visible.
appendix i schedule of evaluations
instructions for blood specimens collected

Blood specimens should be shipped by overnight express at room temperature to:
Sylvia Silver, DA GW Biorepository George Washington Medical Center Ross Hall, Room 118 2300 I St, NW Washington, DC 20037 Phone: (202) 994-2945 Fax: (202) 994-5056 Email: ssilver@gwu.edu
- RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS.  
- Place the box in the FedEx pickup area at your site or call to request a package pickup.  
Please Note: The shippers will be mailed back to each AMC site.  
Preparation of plasma and mononuclear cells Refer to the ACSR's SOP on Separation of Plasma and Mononuclear Cells on the AMC Operations web site for instructions on preparing plasma and PBMC aliquots. It is preferable that separation occurs as soon as possible. If necessary, whole blood in ACD (yellow top tubes) can be held at room temperature for no more than 24 hours. Freeze the cell suspension in 0.5 mL aliquots in sterile NUNC vials by placing the NUNC tubes in a room temperature, alcohol saturated, control rate freezer container and store in the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen temperature freezer for long-term storage the next working day.  
*****PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT**
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice written
appendix i schedule of evaluations
on package. preparation of tissue

Tissue specimens to be fresh frozen should be placed in OCT and then on dry ice immediately. The specimens may stay on dry ice until being transferred to a -80ºC freezer.  
Tissue specimens for donation may be batched for shipping after storage in -80ºC freezer.  
*NOTE: Specimens can only be accepted Monday through **Thursday**. Therefore, specimens can only be shipped **Sunday-Wednesday** for delivery the next day. Shipping frozen tissue requires the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice written on package.  
TISSUE specimens should be shipped by overnight express to:
Sylvia Silver, DA GW Biorepository George Washington Medical Center Ross Hall, Room 118 2300 I St, NW Washington, DC 20037 Tel: (202) 994-2945 Fax: (202) 994-5056 Email: ssilver@gwu.edu
appendix i schedule of evaluations
c. record of specimens

This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all specimen shipments.
appendix i schedule of evaluations
appendix iv acsr informed consent

Study Title for Study Participants: Collecting Blood and Tissue Sample Donations for Research for HIV/AIDS-Related Cancers
Official Study Title: Biospecimen Collection and Donation to the AIDS
and Cancer Specimen Resource (ACSR)
appendix i schedule of evaluations
what is the usual approach

You are being asked to donate blood and/or tissue for future research. You are being asked to donate your blood and/or tissue samples to the ACSR because you have HIV infection and are being considered for participation in an AIDS Malignancy Consortium (AMC) clinical trial. The AMC works with the ACSR to collect donated samples from persons with HIV infection for research studies. People who do not take part in an AMC clinical trial can also donate samples to the ACSR.
appendix i schedule of evaluations
what are my other choices

It is your choice to donate or not donate your blood and/or tissue samples. You may still take part in the AMC clinical study if you choose not to donate blood or biopsy samples to the ACSR. You may also choose to donate:  
- Blood but not tissue, or
- Tissue but not blood.
appendix i schedule of evaluations
what is the aids and

The ACSR is a biorepository (biobank) that collects human biological specimens (samples) from persons who have HIV or cancers related to HIV/AIDS. The ACSR stores the samples and some of the donor's medical information for use by researchers in future research studies. The National Cancer Institute (NCI) has set up the ACSR to assist researchers locate samples needed for their studies. The ACSR has an independent research panel that approves researchers' requests to use the ACSR's stored samples for research studies. The ACSR only gives samples and medical information to researchers after their projects have been approved. Researchers may use the samples to study cancers and other diseases associated with HIV disease. This information may help us learn more about the causes of HIV-related diseases and cancers and to develop better ways to screen, diagnose, and treat them.
appendix i schedule of evaluations
why is this study being

The purpose of this study is to collect samples for the ACSR for future research studies. Researchers may study samples from the ACSR in combination with hundreds or thousands of other samples to explore how biologic or genetic factors may be related to HIV-related diseases and cancer. The information might help doctors in the future to identify who will or will not benefit from treatment. The samples may be used to learn more about how HIV-related diseases and cancers develop. The samples may also lead to new tests or discoveries. Finally, researchers may use the samples to study the genetic material from your cancer tissue and compare it to the material from your normal tissue (blood) to try to find the differences that exist. These studies could make it possible to identify many of the changes that are associated with diseases such as cancers. It may also help us tailor treatments to a patient's unique genetic make-up and/or to the genetic markers of the tumors.
appendix i schedule of evaluations
what extra tests and procedures

1) If you agree to donate blood, the medical team will draw about 2 tablespoons of blood to give to the ACSR. This takes about 10 minutes.  
2) If you agree to donate tissue, your leftover tissue biopsy material will be donated to and stored by the ACSR.  
3) Some of your clinical information will be released to the ACSR and entered into their database.  
The information given to the ACSR will not include your name or any information that could personally identify you.
We will only give the ACSR tissue that is left over after making decisions about your treatment or diagnosis. The study doctor will not take any extra biopsies just for the ACSR. We cannot tell you right now what future research these samples would be used for. Instead, we are asking that you give approval to give your samples for future testing without contacting you again. The results of whatever research is done on your samples will not be told to you or your doctor. The results of the tests will not be placed in your study records.
appendix i schedule of evaluations
how long will acsr keep

Your blood and/or tissue sample will be stored until it is used for research. The samples may be stored indefinitely.
appendix i schedule of evaluations
what possible risks can i

- Blood Draw: The risks of drawing blood include temporary discomfort from the needle stick, bruising, and, rarely, infection.  
- Confidentiality: The ACSR will receive study samples with code numbers. There will be no personal identifiers on the samples. Then the samples will be re-labeled with a barcode and stored for future testing. While the ACSR and researchers who study ACSR samples will have no information that could identify you, there is a risk that someone could use information from genetic studies to trace your samples back to you. The researchers believe the chance that someone will identify you is very small, but the risk may change in the future as people come up with new ways of tracing information. In some cases, this information could be used to make it harder for you to get or keep a job. There are laws against misuse of genetic information, but they may not give full protection. The researchers believe the chance these things will happen is very small but cannot promise that they will not occur.  
Let your study doctor know of any questions you have about these possible risks. You can ask the study doctor questions about side effects at any time.
appendix i schedule of evaluations
what possible benefits can i

This study is unlikely to help you. This study may help us learn things that may help people in the future. The information may help to identify those who are at increased risk and those who may benefit from targeted treatment and screening. In turn, these studies could help find ways to prevent or improve treatments for HIV-related diseases and AIDS-related cancers.  
AMC 097 (Version 9.0) 07FEB2022 110 NCI Version Date 07FEB2022 CLIENT CONFIDENTIAL
appendix i schedule of evaluations
can i stop taking part

Yes, you may withdraw your samples from the ACSR at any time. You may contact your AMC study coordinator if you would like to withdraw your samples. The coordinator can ask in writing that your sample be removed from research use and that any identifiable sample and information still in their possession be destroyed. However, if any research has already been done using some of your samples, the data will be kept and analyzed as part of those studies.
appendix i schedule of evaluations
what are my rights in

Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, there will be no penalty to you. You will not lose medical care or any legal rights. For questions about your rights while in this study, call the ________________________ *(insert* name of center) Institutional Review Board at __________________ (insert telephone number). (Note to Local Investigator: Contact information for patient representatives or other individuals at a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can also be listed here.)
appendix i schedule of evaluations
what are the costs of

There will be no cost to you for donating your samples to the ACSR. You will not be paid for taking part in this study.
appendix i schedule of evaluations
what happens if i am

If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your study doctor. The AMC will not offer to pay for medical treatment for injury. Your insurance company may not be willing to pay for study-related injury. If you have no insurance, you would be responsible for any costs. If you feel this injury was a result of medical error, you keep all your legal rights to seek payment for injury even though you are in a study.
appendix i schedule of evaluations
who will see my medical

Your privacy is very important to us and the researchers will make every effort to protect it. Your information may be given out if required by law. For example, certain states require doctors to report to health boards if they find a disease like tuberculosis. However, the researchers will do their best to make sure that any information that is released will not identify you. Some of your health information, and/or information about your specimen, from this study will be kept in a central database for research. Your name or contact information will not be put in the database. There are organizations that may inspect your records. These organizations are required to make sure your information is kept private, unless required by law to provide information. Some of these organizations are:
- The AIDS Malignancy Consortium (AMC) - The Institutional Review Board, IRB, is a group of people who review the research with the goal of protecting the people who take part in the study.  
- The Office for Human Research Protections and the National Cancer Institute in the U.S.  
To protect your privacy, the AMC does not keep identifying information that links study participants to specific samples. As a result, the AMC and ACSR will not be able to link the results from studies that use your samples back to you. Thus, information, including genetic information, that researchers may obtain in studies that use your samples may not be directly linked to you and will not be placed in your medical record. However, some clinical and basic information obtained confidentially from the AMC will be attached with these data. It is possible that findings may one day help, for example, people of the same race or sex as you. It also is possible that genetic factors might come to be associated with people who have HIV and cancer through these kinds of studies.
appendix i schedule of evaluations
where can i get more

You may visit the NCI Web site at **http://cancer.gov/** for more information about studies or general information about cancer. You may also call the NCI Cancer Information Service to get the same information at 1-800-4-CANCER (1-800-422-6237).
appendix i schedule of evaluations
who can answer my questions

You can talk to the study doctor about any questions or concerns you have about this study or to report side effects or injuries. Contact the study doctor __________________ *(insert name of study* doctor[s]) at __________________ *(insert telephone number).* Please circle your answer to show whether or not you would like to take part in each option: 1) I agree to donate my blood to the ACSR for future research that may be used to learn about, prevent, diagnose, or treat HIV-related diseases and cancer.  
YES NO
2) I agree to donate my blood to the ACSR for future research that may include genetic testing to learn about, prevent, diagnose, or treat HIV-related diseases and cancer.  
YES NO
3) I agree to donate some of my tissue biopsy material that is not required for my treatment or diagnosis to the ACSR for future research that may be used to learn about, prevent, diagnose, or treat HIV-related diseases and cancer.  
YES NO
4) I agree to donate some of my tissue biopsy material to the ACSR for future research that may include genetic testing to learn about, prevent, diagnose, or treat HIV-related diseases and cancer.  
YES NO
appendix i schedule of evaluations
my signature agreeing to take

I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions have been answered. I will be given a signed copy of this form. I agree to take part in the optional study.  
Participant's signature________________________________ Date of signature____________________________________ Signature of person(s) conducting the informed consent discussion________________________ Date of signature_____________________________________
appendix i schedule of evaluations
appendix v consent form for

STUDY **TITLE**: A Pilot Project of Virologic, and Immunologic Correlates of GastrointestinalAssociated Lymphoid Tissue Immune Reconstitution as a Part of Bone Marrow Transplant with Anti-HIV Gene Modified Stem Cells
appendix i schedule of evaluations
introduction

You are being asked if you want to take part in a research study. The main goal of a research study is to learn things to help patients in the future. No one can guarantee that a research study will help you. Participating in research is voluntary. You have the right to know about the procedures, risks, and benefits of the research study. If you decide to take part, you can change your mind later and leave the study. To participate in this study, you will need to give your written consent by signing this form. Please take your time to make your decision and discuss it with your family, friends, and caregivers. A minimum of seven people and a maximum of 18 people will take part in this study at University of California Davis and other AIDS Malignancy Consortium ( AMC) sites.
appendix i schedule of evaluations
why is this study being

We are asking that you take part in a research study of how the immune system in the small intestines improves after your bone marrow transplant with anti-Human Immunodeficiency Virus (HIV-1) gene treated stem cells. We do this by taking biopsies from the part of the intestines just below the stomach. A biopsy is a sampling of small snips of tissue. The samples will be studied in the laboratory. The main purpose of this study is to measure any increase in the number of immune cells in the intestines to see if this number is related to the development of an immune system that is resistant to HIV-1 because of gene therapy. We are asking you to take part in this study because you participated in the Stem Cell Gene Therapy for HIV-1 in AIDS Lymphoma Patients protocol. You must be between the ages of 18 and 60. In order to participate in this study, it will be necessary to give your written consent. Up to 18 people who have participated in the Stem Cell Gene Therapy for HIV-1 in AIDS Lymphoma Patients protocol will take part in this study. Ten volunteers will be HIV-1 negative and will only undergo a single set of procedures called upper endoscopy. This is when the doctor takes an endoscope to look into the intestines and take biopsies that can be taken to the laboratory for testing. Two sets of endoscopies (at approximately 6 months and 8 months after transplant) will be performed.
appendix i schedule of evaluations
before you begin the study

The only additional test you need for this study (above and beyond the tests and exams that you have done) is a short medical history and physical exam by the doctor that performs the study. A blood draw (approximately 1/3 of tablespoon of blood) will also be done by inserting a needle into a vein in your arm to make sure that it is safe to do the endoscopy. We will measure the clotting factors in your blood.  
If you decide to take part in this study, you will be asked to have the screening exams, tests or procedures mentioned above to show that you can continue to be in the study.
appendix i schedule of evaluations
what will happen if i

If you decide to take part in this study, you will be asked to have a procedure called endoscopy. If you are an HIV-1 positive participant, you will be asked to have two sets of endoscopies: at 6 months after the transplant and at 8 months post-transplant. You will also have blood drawn at the time of endoscopy. We will also review your medical records with respect to the HIV-1 infection you have and your treatment for it. Endoscopy uses a small flexible rubber tube (about as big around as a pencil) connected to a video camera to examine the inside of your esophagus, stomach and small intestines. It is commonly used to diagnose and treat many conditions of the upper intestinal tract and we will use this tube to take biopsy samples by inserting a small device into the tube that can take a tiny piece of your gut. All participants will undergo the procedure in the same manner as any other patient having endoscopy. You will receive an IV injection of a pain medication and/or sedative (Demerol or Versed) and be placed on your side. The back of your throat will be numbed using 2% lidocaine gel (like numbing medication used by dentists). An experienced gastroenterologist (specialist in intestinal disease) will pass the flexible endoscope tube into your stomach and intestines. He/She will examine them by looking at the video camera image. He/She will collect biopsy samples (small pieces of tissue about the size of a grain of rice) from your small intestines in several places (up to 24 biopsies total). This tissue will be examined under a microscope and cells will be examined for certain chemicals that are thought to be important in HIV-1 infection. In addition, cells will be examined and counted for T-helper and other types of lymphocytes (the cells affected by HIV-1). Finally, the functions of the cells in your biopsy specimens will be measured and the amount of HIV-1 virus and HIV-1 medication in the specimen will be determined.  
You must be fasting for 12 hours before the endoscopy procedures. You will be asked about your medications before the endoscopy, check with the study doctor or nurse to see if you may take your routine medications during the fasting period. Do not take aspirin, products, containing aspirin or anti-inflammatory agents like Motrin, Advil, or similar non-steroidal anti-inflammatory drugs (NSAID) medications (Tylenol/acetaminophen is permitted) for 7 days before and after the endoscopy procedures. Ask the study doctor what alternatives that you may take. The endoscopy procedure lasts about 30 minutes. You are sedated during the procedure, so it is not uncomfortable. You will be observed for any problems after the procedure and will be given an emergency phone number to call if you experience problems after you leave the endoscopy area. You will need to arrange for transportation to and from the endoscopy procedure so that you do not drive home after the procedure. Any medical observations of clinical importance will be discussed with you and forwarded, in writing, to your treating physician.
appendix i schedule of evaluations
how long will i be

The study is limited to the 2 time points for endoscopy mentioned above. There are no additional studies scheduled after that point.
appendix i schedule of evaluations
what side effects or risks

You may have side effects while on this study. Everyone taking part in the study will be watched carefully for any side effects. However, the researcher may not know all the side effects or risks. Side effects may be mild or very serious. The researchers may give you medicines to help lessen side effects. Many side effects go away. In some cases, side effects can be serious, long lasting, or may never go away. You should talk to the researchers about any side effects that you have while taking part in the study. Risks and side effects related to the procedures we are studying are listed below: Blood draw risks: You will feel some pain when we first insert the tube into your vein. You may have some redness, swelling, or bruising where the tube goes under your skin. In some cases, this type of tube can cause an infection where it goes under the skin. In rare cases, it can cause a blood clot in the vein. Endoscopy risks: The endoscopy is being performed as a part of a research project. The risks of endoscopy are remote, however, there can be pain, gagging, bleeding, infection, perforation (a hole through the bowel wall can occur) and rarely, death can occur. Sedation risks: The risks of intravenous sedation (putting someone to sleep) include bleeding, bruising, pain, infection from intravenous catheter, low blood pressure, decreased breathing, and allergic reaction to the medicine. Allergic reaction risks: Symptoms of allergic reaction may vary from individual to individual but often consists of generalized rash (red skin), itchiness, and a feeling of being excited or anxious. Very rarely swelling of the throat and/or difficulty breathing can accompany these symptoms. Occasionally (rare), midazolam (also called versed, a drug used for sedation) may cause a state of over excitement. The risks for small bowl biopsy are perforation and bleeding. These events have occurred in some patients though not with these physicians. These risks will be explained to you again by in detail prior to the endoscopy procedure by the gastroenterologist.  
Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important to understand that you need to use birth control while on this study. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. There may also be risks to your privacy. The researchers will store study records and other information about you in a secure location and will grant access only to those with a need to know. However, just like with other personal information kept by your health care providers, your banks, and others, even these safeguards cannot guarantee absolute protection of the data. If private information gets into the wrong hands, it can cause harm. Although rare, there are reported cases of breaches that have resulted in discrimination in insurance or employment.
appendix i schedule of evaluations
are there benefits to taking

We do not expect that you personally benefit from participating in this study. However, we may learn more about how immune cells coming from stem cells treated with anti-HIV genes recover after transplant and how it reacts when challenged by HIV-1.
appendix i schedule of evaluations
what are the costs of

There is no charge for you to participate in this study. Neither you nor your insurance carrier will be charged for your taking part in the research. All costs associated with the study including medications and procedures will be paid by the research.
appendix i schedule of evaluations
will my information be kept

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. There are organizations that may inspect your records. These organizations are required to make sure your information is kept private, unless required by law to provide information. Some of these organizations are:
- The AIDS Malignancy Consortium (AMC)  
- The Institutional Review Board, IRB, is a group of people who review the research with the goal of protecting the people who take part in the study.  
- The Food and Drug Administration and the National Cancer Institute in the U.S.
If we access protected health information (for example your medical record), you will be asked to sign a separate form to give your permission. Your medical records may become part of the research record. If that happens, your medical records may be looked at and/or copied by the sponsor of this study and government agencies or other groups associated with the study. Participation in research may involve a loss of privacy, but information about you will be handled as confidentially as possible. A research record will be created because of your participation in this study. Your consent form and some of your research test results will be included in this record. Therefore, your other doctors may become aware of your participation. Hospital regulations require that all health care providers treat information in medical records confidentially. Designated University officials, including the Institutional Review Board, and the Food & Drug Administration have the authority to review research records. If information from the study is published or presented at scientific meetings, your name and other personal information will not be used.
appendix i schedule of evaluations
do i have to participate

Taking part in this study is your choice and completely voluntary. Participation or a decline in participation in this part of the study is independent of your participation in the stem cell gene therapy study. If you decide to take part in this study, you can decide to stop at any time. Leaving the study will not affect your medical. Tell the researcher if you are thinking about stopping or decide to stop so any risks from the can be managed safely.  
The researcher may withdraw you from this research if circumstances arise which warrant doing so even if you would like to continue. We will tell you about new information or changes in the study that may affect your health or willingness to continue in the study.
appendix i schedule of evaluations
will i be compensated for

For the optional intestinal biopsy (upper endoscopy), a fee of $300 for each procedure completed will be paid to you.
appendix i schedule of evaluations
who can answer my questions

If you have questions, please ask us. You can talk to the study doctor about any questions or concerns you have about this study. Contact the study doctor __________________ *(insert name of study doctor[s])* at __________________ *(insert telephone number).* For questions about your rights while in this study, call the ________________________ (insert name of center) Institutional Review Board at __________________ *(insert telephone number).* (Note to Local Investigator: Contact information for patient representatives or other individuals at a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can also be listed here.)
appendix i schedule of evaluations
what happens if i am

If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your study doctor. The study sponsors will not offer to pay for medical treatment for injury.  
Your insurance company may not be willing to pay for study-related injury. If you have no insurance, you would be responsible for any costs. If you feel this injury was a result of medical error, you keep all your legal rights to receive payment for this even though you are in a study. It is important that you promptly tell the person in charge of the research if you believe that you have been injured because of taking part in this study. If you are injured as a result of being in this study, ________________________ *(insert name of center)* will provide necessary medical treatment. Depending on the circumstances, the costs of the treatment may be covered by
________________________ *(insert name of center)*, or may be billed to your insurance company just like other medical costs. The University and the study sponsor do not normally provide any other form of compensation for injury. For more information about compensation, you may call the ________________________ *(insert name of center)* Institutional Review Board at __________________ (insert telephone number).
appendix i schedule of evaluations
my signature agreeing to take

I have read the consent form or had it read to me and understand the information above. I have discussed it with the study doctor and my questions have been answered I understand that I will be given a signed and dated copy of this consent form. I agree to take part in the study. My signature below indicates that I understand my rights and want to take part in this study as a research participant.
appendix vi amc data and
(version 9.0 06oct2020) introduction

The AIDS Malignancy Consortium (AMC) Data and Safety Monitoring Plan (DSMP) outlines the measures employed by the group to monitor the safety of participants and ensure the data validity and integrity for all clinical trials it conducts. This includes methods to: 1) monitor the progress of trials and the safety of participants; 2) comply with regulatory requirements for adverse event (AE) reporting; 3) processes for trial termination or temporary suspension and major modifications; and 4) plans for ensuring data accuracy and protocol compliance. As the AMC conducts protocols of varying research phase, region of conduct (which may include trials conducted in the U.S., international sites, or both), IND sponsor (AMC investigator, CTEP, or industry-sponsored) and clinical data entry system use, this plan addresses broad processes applying to the range of trial designs and requirements. Refer to the individual AMC protocol to identify the applicable study characteristics for the relevant requirements described in this plan.
appendix vi amc data and
monitoring the progress of trials

All AMC protocols that collect safety data adhere to the National Cancer Institute (NCI), Cancer Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements (https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm), as applicable to the clinical protocol. AEs are to be recorded in the source documents, assessed by a clinical investigator for the AE reporting criteria, and promptly reported in the clinical data entry system as required by each protocol. For AMC trials conducted under a CTEP IND and AMC trials conducted within the U.S., all AEs that meet the NCI's expedited reporting requirements are reported to the NCI via the CTEP Adverse Event Reporting System (CTEP-AERS) web application, either directly or through integration with Medidata Rave where this system is employed for AMC protocols. Use of this system ensures notification to the protocol chair and Investigational Drug Branch (IDB) at CTEP, as required for trials conducted under a CTEP IND, and a uniform expedited reporting and safety review process for AMC domestic trials. The system may also be programmed to include sponsor notification as required for trials with industry support. Alternate process for expedited AE reporting to the AMC protocol chairs and AMC Operations and Data Management Center (ODMC) within the clinical data entry system (AdvantageEDC or Advantage eClinical only) may be defined in the protocol for select trials (international studies and The ANCHOR Study). All serious adverse events (SAEs) received by the AMC ODMC will be reviewed by the AMC medical monitor at the AMC ODMC for consideration of individual participant safety, safe trial conduct, data reporting quality for AE term selection, and appropriate application of the regulatory criteria for seriousness, expectedness, and relatedness to the investigational therapy. If alternate procedures are followed for SAE review, the process for adequate medical monitoring will be defined in the AMC protocol and the Transfer of Regulatory Obligations (TORO) with the sponsor. AMC medical monitor review includes review of the CTEP-AERS report before CTEP submission for IDB review (if applicable), or review of the SAE report in the data entry system for trials not using CTEP-AERS for expedited reporting. The IND sponsor or its designee will issue the determination as to whether the AE requires IND safety reporting to FDA as a serious and unexpected suspected adverse drug reaction (SUSAR). For protocols not conducted under an IND, in the event of disagreement between the reporting physician and the AMC medical monitor regarding the relationship of the AE to the investigational agent(s) (i.e., determination of whether the attribution is unrelated or unlikely, or possible, probable, or definite), the AMC medical monitor will provide the final determination of the relationship. IND safety reporting to FDA is performed by CTEP for trials conducted under a CTEP IND; IND safety reporting is performed by the sponsor or sponsor's designee (AMC ODMC or other party defined in the study agreement or TORO) for IND studies sponsored by AMC investigators or industry sponsors. Expedited reporting to the Institutional Review Board (IRB) The requirements for IRB review will be identified in the protocol section on ethical and regulatory obligations. All AMC trials initiated before September 1, 2020 and all international sites for all AMC studies are subject to local IRB review; only U.S. sites are subject to the NCI requirement to use a single IRB for protocols initiated on or after September 1, 2020. For trials subject to local IRB review, the site principal investigator is responsible for ensuring that expedited AE reports for its trial participants and any unanticipated problems that affect the local institution only are submitted to the local IRB of the reporting institution, per the local IRB's requirements for such reporting. For studies reviewed by the single IRB, the protocol chair will render a determination as to whether a SAE or other problem constitutes a trial-wide unanticipated problem that requires reporting to that IRB, in accordance with its standards of procedure. To comply with investigator notification requirements for IND studies under 21 CFR 312.32 and 312.55, IND safety reports from all trials the AMC conducts and reports from external sponsors investigating the same agents are made available to all investigators upon receipt from the sponsor or its designee, either via the password-protected section of the AMC Operations web site (AMC trials subject to local IRB review only) or the CTSU website (U.S. trials subject to single IRB review/CTEP IND agents). The site clinical investigator responsible for the applicable AMC protocol(s) is responsible for reviewing any IND safety reports received and documenting submission to the IRB of record (if required by local policy) within the timeline defined by the Clinical Trials Monitoring Branch (CTMB) audit guidelines.
appendix vi amc data and
procedures for monitoring trial progress

For trials using AdvantageEDC or Advantage eClinical for clinical data entry, the AMC ODMC provides on demand tabular listings of all reported AEs and SAEs on a participant level to the protocol chair and co-chair(s) for review via the password-protected section of the AMC Operations web site, www.AIDScancer.org. For trials using OPEN and Medidata Rave for clinical data collection, data listing will be made available using that system. Summary reports of AEs by frequency and relationship to the investigational agent(s) are provided to all AMC investigators and their staff It is the responsibility of each site to provide trial-specific AE listings to their respective IRB, if required by its policies. For blinded studies, the AE and SAE listings are reviewed and tabulated without treatment assignment. Accrual summaries for each AMC trial are updated nightly on the password-protected section of the AMC web site. The progress of each AMC trial is reviewed regularly by the protocol chair and also by the appropriate Scientific Working Group (SWG) during scheduled conference calls (monthly SWG calls and as required, protocol-specific monitoring conference calls). Summary accrual, summary AE, and individual SAE reports are provided to SWG leadership and protocol chairs to monitor participant safety during these monthly calls. The AMC medical monitor reviews listings of all reported AEs on a quarterly basis for assuring compliance with the protocol requirements for AE reporting and the identification of any safety concerns (individual AE or increased frequency/severity of expected AEs) for the agents under investigation. Findings from these reviews are communicated to the protocol chairs and all AMC investigators, and posted to the AMC Operations web site.
appendix vi amc data and
data and safety monitoring board

The AMC has formed an independent Data and Safety Monitoring Board (DSMB) for AMC trials and for the ANCHOR Study. As required by NCI policy, the AMC requires DSMB review for all phase III randomized trials. All other clinical trials that the AMC initiates will be reviewed by the AMC ODMC and AMC Statistical Center during protocol development to issue a recommendation as to whether the study requires DSMB oversight, which will require the approval of the AMC Executive Committee. This determination will be based on the phase of the study, experimental design, risk posed by the investigational approach, extent of data available on the safety of an investigational agent, risk posed by the natural course of the health condition under research, and the categories of vulnerable populations involved. The involvement of a DSMB in reviewing an AMC protocol will be identified in each clinical protocol as approved by CTEP and, as applicable, required by the IRB of record. Regarding the composition of the AMC DSMB, voting members usually include physicians, statisticians, an ethicist, and a patient advocate. All voting members have no other affiliation to the AMC and are appointed by the AMC Executive Committee with the approval of the OHAM Director. Nonvoting members are the AMC group statistician, the protocol statistician, an AMC ODMC staff member, two representatives (normally a clinician or statistician) from CTEP, and the grant program directors from the NCI Office of HIV and AIDS Malignancy (OHAM). The DSMB reviews all applicable AMC studies in accordance with the National Cancer Institute's Policy for Data and Safety Monitoring. Confidential reports of all trials under review are prepared by the AMC group statistician with support from the AMC ODMC. A written report containing the current status of each trial monitored, and when appropriate, any toxicity and outcome data, are sent to DSMB members by the AMC ODMC within the timelines specified by the DSMB charter. This report addresses specific toxicity issues and any other concerns about the conduct of the trial, as defined by the protocol plan for DSMB review. The report may contain information for the DSMB to render determinations for participant safety, early trial termination, results reporting, or continuing accrual or follow-up. The results of each DSMB meeting are summarized in a formal report sent by the DSMB chair to the AMC group chair and AMC ODMC. The DSMB report contains recommendations on whether to close each study reviewed, whether to report the results, and whether to continue accrual or follow-up. A primary recommendation (e.g., continue with no change; recommended or required modification; stop) must be included in the document. The group chair or designee is then responsible for notifying the protocol chair and relevant SWG chair before the recommendations of the DSMB are carried out. In the unlikely event that the protocol chair does not concur with the DSMB, then the OHAM program directors and the NCI division director or designee must be informed of the reason for the disagreement. The protocol chair, relevant SWG chair, group chair, DSMB chair, and NCI division director or designee will be responsible for reaching a mutually acceptable decision about the study. CTEP approval of a protocol amendment will be required prior to any implementation of a change to the study. Following a DSMB meeting, the DSMB's recommendations are provided to all AMC investigators and staff. It is each site principal investigator's responsibility for conveying this information to its local IRB as relevant for its protocol participation. For trials reviewed by a single IRB, the AMC ODMC will support notification to the IRB as required per its procedures. Cohort trial reviews not subject to DSMB review For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in the protocol and the protocol chair, AMC medical monitor, and protocol statistician determine whether these criteria have been met based on a review of all safety data for the protocol-defined evaluation period. If applicable for phase II trials, stopping the trial for toxicity or efficacy, or suspending enrollment pending observation of responses in a multi-stage phase II trial, is based on meeting criteria stated in the protocol, and the protocol chair, AMC medical monitor, and protocol statistician determine whether these criteria have been met.
appendix vi amc data and
plans for assuring compliance with

The protocol chair, AMC group chair, and the AMC ODMC share responsibility in assuring that participating investigators comply with applicable regulatory and protocol requirements for AE reporting. The AMC site principal investigator certifies compliance with NCI and FDA requirements for trial conduct by signing the site subaward agreement for the grant and the AMC Adherence Statement for site membership; clinical investigators also certify compliance in completing the protocol signature page for each protocol active at the site, and Form FDA-1572 for CTEP investigator registration, and also for AMC IND studies sponsored by AMC investigators or industry sponsors. Protocol compliance with AE identification, assessment and reporting requirements is assessed by the AMC ODMC using several methods: 1) programmed system checks and messages to instruct the site to complete routine and/or expedited reporting when certain criteria are reported in the clinical data entry system; 2) programmed data reports provided to the protocol chairs that identify reports requiring expedited AE reporting; 3) remote review of data entry or data reports to ensure compliance with protocol and NCI AE reporting requirements; 4) AMC medical monitor review described in the section above; and, 5) routine site audits by reviewing the site's source documentation. The clinical data entry systems used for AMC studies include the Oncology Patient Enrollment Network, OPEN for enrollment, and Medidata Rave for clinical data entry for enrolled participants; trials activated before September 1, 2020 or that involve only AMC international sites may be reported in AdvantageEDC/Advantage eClinical, a web-based data entry and enrollment system. These data entry systems are programmed to notify the site investigator, protocol chair, AMC medical monitor, and AMC ODMC via email in the event that a site reports an AE that meets expedited reporting criteria to NCI and/or FDA. Additional reporting conditions may be programmed depending on the sponsor reporting requirements of a given protocol (e.g., adverse events of special interest [AESI]). If the site does not follow with an expedited report, the AMC ODMC contacts sites to request compliance with reporting requirements. Additionally, the protocol chair, AMC ODMC, and the AMC medical monitor review reported AEs on a routine basis to identify AEs reported by sites that require expedited reporting. The protocol chair, AMC SWG chairs, AMC group chair, and IND sponsors have general oversight for assuring that routine and expedited adverse reporting requirements are met by the responsible parties. For studies monitored by CTEP using the Data Mapping Utility (DMU), cumulative protocol- and patient-specific data will be submitted weekly to CTEP electronically via the DMU. For trials monitored by the NCI's Clinical Data Update System (CDUS), AE information is transmitted electronically to NCI on a quarterly basis. For trials monitored by NCI's Clinical Trials Monitoring Service (CTMS), AE information is transmitted electronically to NCI every two weeks. Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible
appendix vi amc data and
for the grant

In the event that temporary or permanent suspension of a trial, or major modification to the protocol is under consideration, the protocol chair will convene the AMC ODMC, AMC Statistical Center, and SWG chair by conference call to discuss the options. Suspension actions will also be reviewed by the AMC Executive Committee for program oversight and direct communication of the action with the OHAM program directors. For phase III trials, closure decisions are typically rendered by the AMC DSMB; if the trial in question is under AMC DSMB oversight but rendered by the AMC investigators, the AMC DSMB will be notified of the suspension and the reason. For phase I and II trials, the protocol chair also has the option of asking the DSMB to review the study. The AMC ODMC will inform the CTEP Protocol Information Office (PIO), with copy to OHAM Directors, when studies are temporarily or permanently closed. In the event of major trial modification, CTEP must approve all protocol amendments prior to distributing to the AMC sites.
appendix vi amc data and
plans for assuring data accuracy

All study data for AMC clinical trials are entered directly by AMC clinical site staff into the applicable clinical data entry system for the trial. During data entry, the system performs validation checks on many fields and performs consistency checks between select fields. Range checks are placed on each field to eliminate entry of out-of-range values. Edit check programs are run on the database on a set schedule to identify and resolve inconsistencies between forms or data collected at different points in time. Submitted data entry forms are reviewed for compliance with the protocol and data entry instructions according to the AMC ODMC's standards for data quality processes. AMC ODMC staff routinely interacts with site staff to resolve any data submission problems. In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to evaluate compliance with regulatory issues, and to review data for specific cases by checking source documents. These reports are sent to the site principal investigator and to the NCI. In the event that major violations are identified, sites are asked to provide a written corrective and preventative action plan to correct deficiencies. If needed, a repeat site audit is conducted. In the event that a site does not correct deficiencies in a pre-determined time frame, the AMC Executive Committee has the option to implement remedial action(s) for the site. Possible actions include, but are not limited to, suspending enrollment of new patients to AMC trials until deficiencies are corrected; recommending a decrease in funding to the site; and requiring specific training for site investigators or staff members.