5. TREATMENT PLAN 5.1 Agent Administration The patients will receive 10 μg/kg of CYT107 every week for 4 weeks, beginning between 3 to 7 days (3 days preferred) after completion of standard sipuleucel -T therapy (i.e., after the NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 21 third and final dose of sipuleucel -T). At 10 -20 µg/kg, some specific immune response or antiviral activity has been documented. CYT107 will be administered subcutaneously, which according to studies in monkeys, yields satisfactory bioavailability (> 75%), with an extended kinetic profile that may favor prolonged CYT107 activity. REGIMEN DESCRIPTION Agent Dose Route Schedule Treatment Phase CYT107 (cohort 1) No therapy (observation) 28 days (4 weeks) CYT107 (cohort 2) 10 μg/kg Subcutaneous Dose 1: (day 0) 3 -7 days post sipuleucel -T Dose 2: (day 7) 10 -14 days post sipuleucel -T Dose 3: (day 14) 17 -21 days post sipuleucel -T Dose 4 (day 21) 24 -28 days post sipuleucel -T Patients assigned to observation (cohort 1) and patients assigned to receive CYT107 (cohort 2) will follow the same study procedures and blood collection schedule . However, the study visits on Week 2 (Day 7) and Week 4 (Day 21) are optional for patients assigned to observation (cohort 1). All patients randomly assigned to receive CYT107 (cohort 2) will remain under observation for 4 hours after each injection of CYT107 (Day 0, Day 7, Day 14 and Day 21). The vital signs will be monitored every 2 hours and patients will be observed for the development of any allergic reaction to the CYT107, such as hives, bronchospasm, rash, etc. The first six patients randomly assigned to receive CYT107 will be followed for an additional 4 weeks prior to the study expanding past six patients, as a lead -in phase to ensure safety and tolerability of the selected CYT107 dose . In order to continue enrollment, only one grade 3 or 4 Adverse Ev ents related to CYT107 is allowed with the exception of transient lymphopenia (See Section 6 ). For the purpose of evaluating the first 6 patients, a Grade 3 or 4 ‘lymphocyte count decrease’ will be count ed as an Adverse Event towards stopping enrollment, only if the count fails to return to a minimum of 500 cells/mm3 by the time of the scheduled start of the next cycle. Patients must complete standard sipuleucel -T therapy before receiving the CYT107 dose s. The standard, FDA approved, sipuleucel -T therapy is three vaccinations administered on days 0, 14 and 28. CYT107 must be administered within 3 to 7 days of the patient receiving their last sipuleucel -T (Provenge®) vaccination. Patients may not use any of the following therapies during the administration of CYT107:  Concomitant systemic or local anti -cancer medications or treatments (investigational or non -investigational) are prohibited in this study while receiving CYT107 treatments.  Treatmen t with hormones or other chemotherapeutic agents may not be administered except for hormones administered for non -disease -related conditions (e.g., insulin for NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 22 diabetes mellitus). Neoadjuvant chemotherapy and chemotherapy given for hormone sensitive prosta te cancer are allowed.  Therapy with anti -androgens must be stopped for at least 30 days prior to first CYT107 injection.  Palliative radiation therapy may not be administered during protocol treatment.  Immunosuppressive agents including chronic systemic corticosteroids, except for those directed by the protocol or for toxicities such as hypersensitivity or other immune events.  Any non -oncology vaccine therapies used for the prevention of infectious diseases (for at least 30 days prior to or after any do se of study drug). Patients may continue to receive the following:  Continued LHRH agonist or antagonist therapy is allowed and is mandatory, except for pa tients with prior orchiectomy.  Continued bone targeted agents (e.g. zolendronate, denosumab ) are allowed  Patients should receive full supportive care, including transfusions of blood and blood products, erythropoietin, antibiotics, antiemetics, etc. when appropriate. After the period of CYT107 administration, patients should not receive additional prostate cancer therapies until or unless substantial progression occurs. Therapies should be held until after day 70 if medically appropriate in the view of the primary treating physician. Adverse events noted following subsequent therapies wit hin the 5 3 weeks duration of follow -up will be chronicled and attribution assessed. 5.1.1 CTEP IND Agent: N/A 5.1.2 Other Agent(s): N/A 5.1.3 Other Modality(ies) or Procedures: N/A 5.1.4 Investigational Imaging Agent Administration: N/A 5.2 Definition of Dose Limiting Toxicity: N/A 5.3 General Concomitant Medication and Supportive Care Guidelines Studies performed to investigate the potential of CYT107 to inhibit or to act as a time dependent inhibitor of hepatic microsomal cytochrome P450 is ozmyes ( see Investigator Brochure) concluded that at the concentration investigated, it is unlikely that CYT107 will be involved in drug -drug interactions and CYT107 is not expected to cause clinically significant P450 inhibition or induction. However, the case report form must capture the concurrent use of all other drugs, over -the-counter medications, or alternative therapies including vitamins and nutritional supplements. NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 23 5.4 Duration of Therapy In the absence of treatment delays due to adverse event(s), treatment may continue for one cycle ( 4 doses total) or until one of the following criteria applies:  Unacceptable adverse event(s)  Intercurrent illness that prevents further administration of treatment  General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator  Disease progression  Patient decides to withdraw from the study 5.5 Duration of Follow Up Patients will be followed for 5 3 weeks or until death, whichever occurs first. Patients, in whom therapy is stopped due to unacceptable adverse event(s) will continue to be followed for 5 3 weeks or until resolution or stabilization of the adverse event if that takes more than 53 weeks. Many patients will receive additional therapy for progression within the 5 3 weeks duration of follow -up. Additional therapy will be chronicled. Patients will be asked to be followed by phone, once a year, after completion of Week 53. Overall Survival data wi ll be collected and reported (see Section 11.1 ) until the end of the study. 5.6 Criteria for Removal from Study Patients will not be removed from the study; however the patient may decide to withdraw from the study at a ny time. Patients with Adverse Events or progression will continue to be followed for a total of 5 3 weeks. If the patient elects to leave the study, notify the Principal Investigator, and document the reason for study removal and the date the patient was removed in the Case Report Form. The patient should otherwise be followed per protocol requirements. 5.7 Laboratory Specimen collection The Study Calendar in section 10 outlines the timing of procedures and follow up visits. The CITN12 -03 Laboratory Manual outlines the timing of blood draws as well as the maximum total amount of the blood draws. Quantity of Blood Draws: The maximum total blood draw on weeks 1, 6, 11, 23, and 53 is between 2 76 and 2 86 mL. Due to the large quantity of blood scheduled to be drawn at these visits, assessment for anemia is necessary. Based on the safety laboratories the volume of blood drawn at weeks 1, 6, 11, 23, and 53 will be determined . NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 24 Inclusion criteria demand a hemoglobin (Hgb) of ≥10 g/dL for entry into the study. Thus, profound anemia is not likely to be an issue. If a substantial drop in Hgb is observed , patients should be assessed for cryptic bleeding and hemolysis. If Hgb is <10g/dL prior to the Week 1 Day 0, Week 6 Day 35, Week 11 Day 70, Week 23 Day 154 or Week 53 Day 365 visits, less than the maximum total volume of blood should be drawn as follows:  On Week 1 Day 0, i f the Hgb is ≥9 g/dL, up to 9.9 g/dL, then blood draw amounts may be decreased to 2 26 mL (from 286 mL), on Week 1 Day 0.  On Week 6 Day 35 and Week 11 Day 70 , blood dr aw amount may be decreased to 2 16 mL (from 2 76 mL).  On Week 23 , blood draw amount may be decreased to 2 20 mL (from 2 70 mL)  On Week 53 Day 365 , blood draw amount may be decreased to 2 26 mL (from 2 86 mL ). If the Hgb is less than 9 g/dL, drawing blood only for local safety labs is recommended. If a site is unable to collect all specimens due to low hemoglobin or other issues such as vein access, specimens should be collected in the following order if required at the visit: 1) Toxicity/safety specimens and local safety labs 2) ELISA 3) ELISPOT and other cellular assays 4) Other assays If the Hgb is > 10 all labs will be drawn. 6. DOSING DELAYS/DOSE M ODIFICATIONS The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used to grade adverse events. Patients enrolled in this study will be evaluated clinically and with standard laboratory tests before and at regular intervals during their participation in this study as specified in this section. Patients will be evaluated for adverse events (all grades), serious adverse events, and adverse events requiring study drug interruption or discontinuation at each study visit for the duration of their participation in the study. Delays in dosing will be allowed for delays such as weather factors resulting in delays getting to the clinic or hospital, travel delays, clinic schedules or emergencies. A delay of up to 72 hours will be allowed on one occasion during the course of a treatment cycle. Removing patients from protocol therapy for Adverse Events : Patients will come off protocol therapy if any grade 3 or 4 Adverse Events by CTCAE Version 4.0 criteria occur with the exception of transient lymphopenia. Three cases of Grade 3 lymphopenia have been documented with CYT107. For purposes of this trial, since peripheral lymphopenia is a transient event, a Grade 3 ‘lymphocyte count decrease’ to <500 -200 cells/mm3 and a Grade 4 ‘lymphocyte count decre ase’ to <200 cells/mm3 will not require patients coming off protocol provided the lymphocyte count returns t o a minimum of 500 cells/mm3 by the time of the scheduled start of the next weekly dose within the treatment phase. A Grade 3 or 4 ‘ lymphocyte count decrease’ NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 25 will require patients coming off protocol if the count fails to return to a minimum of 500 cells/ mm3 by the time of the scheduled start of the next cycle. Dose modifications for Adverse Event s: Substantial adverse events are not expected and thus dose modifications are not planned or recommended with the exception of fatigue (see below). In initial h uman trials with CY T107 adverse events were frequent, but transient and grade 2 or less (as noted in the Adverse Event list, section 7.1.2.). These include erythema or local reaction at site injection, peripheral adenopathies next to the site injection, ra sh, general reactions of fever and flu -like symptoms. Fatigue was infrequent ; dose modification for this event is noted below: Event Name Nausea Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule Grade 3 Off protocol therapy if with adequate/maximal medical intervention symptoms persist Grade 4 Off protocol therapy Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Anti -emetics Event Name Vomiting Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule Grade 3 Off protocol therapy if with adequate/maximal medical intervention symptoms persist Grade 4 Off protocol therapy Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Anti -emetics Event Name Diarrhea Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule Grade 3 Off protocol therapy if with adequate/maximal medical intervention symptoms persist Grade 4 Off protocol therapy Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Physician discretion Event Name Neutropenia Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule Grade 3 Hold* until ≤Grade 2. NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 26 Grade 4 Off protocol therapy *Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Treatment of infection as appropriate Event Name Thrombocytopenia Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule Grade 3 Off protocol therapy Grade 4 Off protocol therapy Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Platelet transfusions if indicated Event Name Fatigue Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule Grade 3 Hold* until ≤Grade 2. Grade 4 Off protocol therapy *Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Physician discretion Event Name Hepatic damage Grade of Event Management/Next Dose of CYT107 ≤ Grade 1 No change in dosing schedule Grade 2 No change in dosing schedule1 Grade 3 Off protocol therapy Grade 4 Off protocol therapy *Patients requiring a delay of >72 hours should go off protocol therapy. Recommended management: Physician discretion Note : 1CYT107 will be discontinued if patients have a concurrent elevation of ALT >3 x upper limit of normal (ULN) and total bilirubin > 2 x ULN in whom there is no evidence of biliary obstruction or other causes that can reasonably explain the concurrent elevation. 7. ADVERSE EVENTS: LIS T AND REPORTING REQU IREMENTS Adverse event (AE) monitorin g and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1.2 ) and the characteristics of an observed AE ( Section 7.2) will determine whether the event requires expedi ted reporting (via CTEP -AERS ) in addition to routine reporting. 7.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) : N/A 7.1.1 CAEPRs for CTEP IND Agent(s): N/A NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 27 7.1.2 Adverse Event List for CYT107 IL-7 Tabular summary of adverse drug reactions for all clinical trials (as of May 2012) (See Investigator Brochure) CYT107 (N = 256) Events Grade Frequency Transient events observed whatever the dose Erythema or local reaction at site injection Grade <1, 1 and 2 Frequent: approximately 2/3 of patients, mostly less than Grade 1 or Grade 1 Peripheral adenopathies next to the injection site Grade 1 Grade 2 Frequent, but transient Rare (1 case) Transient events observed dependent on the dose administered General reactions: Fever, Flu -like symptoms Grade 1 or 2 Uncommon Rash Grade 1 or 2 Grade 3 Rare 2 cases Fatigue (PT in MedDRA), reported as “Asthenia” by investigative team Grade 1 or 2 Grade 3 Uncommon Rare (1 case) Hepatic damage (cytolysis and/or cholestasis) ALT and/or AST elevation Grade 1 or 2 Grade 3 Grade 4 Uncommon 2 cases Rare (1 case) Peripheral lymphopenia Grade 1 or 2 Grade 3 Uncommon 3 cases Anaphylactic Reaction Grade 3 Uncommon Other events Chest pressure Grade 2 Rare (1 case) Immunogenicity Non applicable Frequent: about 25% Isolated transient HIV RNA VL “blips” (in patients Known to be HIV positive) Mostly Grade 1 Uncommon (31 events/590 measurements or 0.05%) Phlebitis Grade 3 Rare (1 case) Henoch -Schoenlein Purpura Grade 2 Rare (1 case) Lichen Planus Grade 3 Rare (1 case) 7.1.3 Adverse Event List(s) for Commercial Agent(s): N/A 7.1.4 Adverse Event List(s) for CIP ( e.g. Study -Specific) Commercial Imaging Agents: N/A 7.2 Adverse Event Characteristics  CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A co py of the CTCAE NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 28 version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm .  Attribution of the AE: - Definite – The AE is clearly related to the study treatment. - Probable – The AE is likely related to the study treatment. - Possible – The AE may be related to the study treatment. - Unlikely – The AE is doubtfully related to the study treatment. - Unrelated – The AE is clearly NOT related to the study treatment. 7.3 Expedited Adverse Event Reporting 7.3.1 Expedited AE reporting for this study must use CTEP -AERS (CTEP Adverse Event Reporting System), accessed via the CTEP Web site ( http://ctep.cancer.gov ). The reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP W eb site (http://ctep.cancer.gov ). These requirements are briefly outlined in the tables below (Section 7.3.3 ). In the rare occurrence when Intern et connectivity is lost, a 24 -hour notification is to be made to CTEP by telephone at 301 -897-7497. Once Internet connectivity is restored, the 24-hour notification phoned in must be entered electronically into CTEP -AERS by the original submitter at the s ite. 7.3.2 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. 7.3.3 Expedited Reporting Guidelines Use the NCI protocol number and the protocol -specific patient 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 “Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 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. NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 29 Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) An adverse event is considered serious if it results in ANY of the following outcomes: 1) Death 2) A life -threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persis tent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may b e considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP - AERS 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: o “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. o “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 com plete 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 2For 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 7.3.4 Additional Protocol -Specific Expedited Adverse Event Reporting Exclusions: N/A 7.3.5 Serious Adverse Event Reporting to the Industry Partners The Sponsor will provide the industry partners with SAE Reports that are sent to the FDA. All SAE reports will include the investigator’s assessment of causality. NCI Protocol #: CITN12 -03 Version Date: July 26, 2017 30 7.4 Routine Adverse Event Reporting All Adverse Events must be reported in routine study data submissions. AEs reported through CTEP -AERS must also be reported in routine study data submissions. 7.5 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 via CTEP -AERS . Three options are available to describe the event:  Leukemia secondary to oncology chemotherapy ( e.g., acute myelocytic l eukemia [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. 7.6 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 reporting via CDUS unless otherwise specified. 8.