A Phase 1/2 , Placebo -Controlled, Randomized Study to Evaluate the Safety, Immune Response and Clinical Activity of HS -410 in Patients with Non-Muscle Invasive Bladder Cancer Who Have Undergone Transurethral Resection of Bladder Tumor (TURBT) Protocol HS410 -101 Amendment History: Date Version Amendment Number Amendment Type 25 Sep 2013 1.0 Initial Protocol Not applicable 5 Nov 2013 2.0 1 Non-substantial 18 Feb 2014 3.0 2 Substantial 26 June 2014 4.0 3 Substantial 28 Oct 2014 5.0 4 Non-substantial 23 Feb 2015 6.0 5 Substantial 22 Apr 2015 7.0 6 Substantial 03 Feb 2016 8.0 7 Substantial CONFIDENTIAL Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the execution of the ethical review of the study, without written authorization from the sponsor. It is however, permissible to provide information to a participant to obtain informed conse nt. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 2 of 86 Sponsor: Melissa Price, PhD Heat Biologics, Inc. 801 Capitola Drive, Suite 12 Durham , NC 27 713 Tel: 919 -240-7133 Medical Monitor: Pia Lynch , M.D. Drug Safety Solutions 5205 Indigo Moon Way Raleigh, NC 27613 Tel: 770-826-1096 Fax: 678-828-5549 Primary Investigator: Gary D. Steinberg, M.D. The Bruce and Beth White Family Professor and Director of Urologic Oncology Vice Chairman Section of Urology University of Chicago Medical Center 5841 S. Maryland Avenue, MC 6038 Chicago, Illinois 60637 Tel: 773 -702-3080 Fax: 773 -702-1001 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 4 of 86 INVESTIGATOR PROTOCOL AGREEMENT PAGE Protocol Number: HS410 -101 Protocol Title: A Phase 1/2, Placebo -Controlled, Randomized Study to Evaluate the Safety, Immune Response and Clinical Activity of HS-410 in Patients with Non-Muscle Invasive Bladder Cancer Who Have Undergone Transurethral Resection of Bladder Tumor (TURBT) Version/Date: Version 8.0 (03 Feb 2016 ) I understand that all documentation provided to me by Heat Biologics, Inc., or its designated representative(s) concerning this study that has not been published previously will be kept in the strictest confidence. This documentation includ es the study protocol, investigator’s brochure, case report forms, and other scientific data. This study will not commence without the prior written approval of a properly constituted Institutional Review Board (IRB) and Institutional BioSafety Committee ( IBC) , as applicable . No changes will be made to the study protocol without the prior written approval of Heat Biologics, Inc., and the IRB and/or IBC, except where necessary to eliminate an immediate hazard to the patient. I have read and understand the c linical protocol and agree to conduct the clinical study in compliance with the protocol, Good Clinical Practice, the Declaration of Helsinki (2008), United States and other applicable local regulatory requirements. Principal Investigator Name, printed: ____________________________________________ Principal Investigator Signature:_________________________________________________ Date: ________________________ Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 5 of 86 CLINICAL PROTOCOL SYNOPSIS Trial title: A Phase 1/2, Placebo -Controlled, Randomized Study to Evaluate the Safety, Immune Response and Clinical Activity of HS -410 in Patients with Non -Muscle Invasive Bladder Cancer Who Have Undergone Transurethral Resection of Bladder Tumor (TURBT) Study objectives: Primary Objective:  Phase 1: To characterize the safety and tolerability of low dose monotherapy vaccination with vesigenurtacel -L in patients with non-muscle invasive bladder cancer .  Phase 2: o Arms 1, 2 , and 3 : To evaluate 1-year disease -free survival in patients with non-muscle invasive bladder cancer treated with BCG in combination with blinded study product (one of two doses of vesigenurtacel -L or placebo ). o Arm 4: To evaluate 1-year disease -free survival in patients with non -muscle invasive bladder cancer treated with high dose vesigenurtacel -L monotherapy. Secondary Objectives:  To evaluate the safety of the combination of vesigenu rtacel -L and BCG (Phase 2 only)  To evaluate the safety of high dose vesigenurtacel -L monotherapy (Phase 2 only)  To evaluate the proportion of patients with recurrence at 3, 6, 12, 18, and 24 months  To evaluate the p roportion of patients with progressive disease at 3, 6, 12, 18 , and 24 months  To evaluate disease -free survival at 3, 6, 18 and 24 months  To evaluate overall disease -free survival  To evaluate o verall survival (OS)  To evaluate the proportion of patients undergoing post-treatment TURBT or fulguration by 12 and 24 months  To evaluate the proportion of patients undergoing cystectomy by 12 and 24 months  To evaluate the proportion of patients with immunologic response of PBMCs via intracellular cytokine staining (ICS) by flow cytometry and/or ELISPOT on CD8+ cells following vesigenurtacel -L vaccination Exploratory Objectives :  Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, CD19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of IFNγ and granzyme B (gzB) .  Total PBMC counts by flow cytometry , including lymphocyte subsets ( B cells, helper T -cells, cytotoxic T -cells, NK cells and T -reg)  Evaluation of tumor tissue obtained prior to treatment for antigen expression , expression of major histocompatibility complex (MHC) class I, and expression of immunosuppressive molecules  Evaluation of tumor tissue obtained from repeat biopsy , if clinically indicated, for presence of tumor infiltrating T -lymphocytes (TILs)  T cell receptor sequencing of PBMCs and tumor tissue to determine correlation between clonally expanded T cell populations and other endpoints  Immune cell infiltration and inflammatory cytokine levels in urine (Phase 2 only) Trial centers: Up to 20 centers Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 6 of 86 Sample size: Approximately 110 patients will be enrolled in the study in order to obtain 10 patients in Phase 1 and 100 patients in Phase 2 . Trial design: Patients with non -muscle invasive bladder cancer who have either undergone TURBT or fulguration for the removal of papillary disease or who have carcinoma in situ (CIS) only, are candidates for BCG treatment, and are judged to be at an increased risk for recurrence are eligible if they are BCG naive or have completed previous BCG treatment >12 months prior to the baseline stagin g procedure . Phase 2 also allows patients who will not otherwise receive BCG. The Phase 1 portion is an open -label, safety study consisting of one cohort with 10 patient s. Patients will have previously received 3 -6 instillations of weekly intravesical BCG induction therapy (as standard of care) followed by low dose intradermal (1 x 106 cells) vesigenurtacel -L (HS-410) monotherapy. In Phase 2 , patients will be assigned to treatment gr oups based on whether they will receive induction BCG in the typical post -TURBT window . If the investigator plans to administer BCG, patients will be randomized to one of three blind ed (physician -patient) , placebo - controlled groups and receiv e either intradermal placebo or low dose or high dose (1 x 107 cells) vesigenurtacel -L in combination with induction and maintenance intravesical BCG. If patients will not receive BCG, they will be enroll ed into an open -label , non -randomized group an d receive high dose intradermal vesigenurtacel -L monotherapy . Phase 1 : Patients enrolled in the first cohort within 8 -10 weeks of TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS only, and after induction BCG will be treated with vesigenurtacel -L weekly for 6 weeks. After a one-week vaccine holiday for disease assessment , patients will receive vesigenurtacel -L for an additional 6 weeks followed by three once monthly treatments for a total of 15 vaccinations . Patients will be observed weekly to assess the safety of vesigenurtacel -L. Dosing of the first three patients will be staggered by two-week intervals to allow for safety evaluation before treating additional patients. If vesigenurtacel -L appears safe and well -tolerated in the 3 lead - in patie nts, dosing will be continued to 10 patients. Phase 2 : Dosing in Phase 2 will begin when all 10 patients have been dosed in the Phase 1 cohort, at least 6 patients in that cohort have completed the Week 7 safety assessments, and the Data Monitoring Committee (DMC) has met to review this data and agree d it is safe to advance to Phase 2. A total of 100 patients will be assigned to four groups: 75 who will receive BCG will be randomized to arms combining either low dose vesigenurtacel -L, high dose vesigenurtacel -L, or placeb o, respectively, with induction and maintenance BCG ; 25 who will not receive BCG will be enrolled in the high dose vesigenurtacel -L monotherapy arm. In the randomized arms, t reatment will commence within 6 weeks of the most -recent TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS only. Patients will be treated during an induction phase with weekly intravesical BCG and intradermal blinded study product (vesigenurtacel -L or placebo ) for 6 weeks followed by 6 weekly injections of blinded study product alone. During a subsequent maintenance phase, patients will receive an additional three courses of three once -weekly blinded study product injections in combination with intravesical BCG appr oximately 3, 6, and 12 months after initiating induction BCG. Patients may receive additional courses of maintenance BCG in long -term follow -up at the investigator’s discretion but should not receive any other cancer therapy prior to disease recurrence /progression . Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 7 of 86 Trial d esign (con ’t): In the monotherapy arm, treatment will commence within 6 weeks of the most -recent TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS only . Patients will be treated during an induction phase with weekly intradermal vesigenurtacel -L for 12 weeks. During a subsequent maintenance phase, patients will receive an additional three courses of three once -weekly vesigenurtacel -L injections approxim ately 3 , 6, and 12 months after initiating induction vesigenurtacel -L. All patients in both the Phase 1 and Phase 2 portions of the study will have a cystoscopy and cytology and , if clinically indicated, a biopsy performed approximately every 3 months for 2 years then every 6 months for up to a year, study termination, disease progression, or recurrence requiring treatment discontinuation, whichever occurs first. Patients with evidence of disease at an assessment may continue on treatment if judged by the investigator to be in the patient’s best interest (e.g. would normally receive another course of BCG therapy as standard of care (SOC)). Upon discontinuation of study treatment, additional treatment will be at the discretion of the treating physician per SOC. While treatment may continue in the presence of evidence of disease, statistical analysis of disease -free status will still follow strict definitions as defined in section 10.1. Evaluation of Disease . Dosing regimen: Phase 1 : Patients will receive weekly intradermal injections of low dose vesigenurtacel -L (1 x 106 cells per dose) for 12 weeks with a vaccine holiday on Week 7 to allow for assessment of evidence of disease, followed by three once -monthly injections for a total of 15 doses. Phase 2 : In the randomized arms, p atients will receive weekly intradermal injections of blinded study drug product (one of two doses of vesigenurtacel -L or placebo ) in combination with intravesical induction BCG for 6 weeks followed by 6 weeks of blinded study product monotherapy with a vaccine holiday on Week 13 to allow for assessment of evidence of disease, followed by three courses of three once -weekly injections of blinded study product in combination with maintenance BCG for a total o f 21 d oses. Vesigenurtacel -L: Arm 1: Vesigenurtacel -L consisting of 1 x 106 cells per dose Arm 2: Vesigenurtacel -L consisting of 1 x 107 cells per dose Arm 3: Placebo BCG: A full dose according to the investigator’s standard practice should be administered. In the monotherapy arm (Arm 4), patients will receive weekly intradermal injections of high dose (1 x 107 cells per dose) vesigenurtacel -L for 12 weeks, followed by t hree courses of three once -weekly vesigenurtacel -L injections for a total of 21 doses. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 8 of 86 Dosage form and route Each study product dose will be divided into the number of injections required to reach the number of cells per dose with no more than 0.1 mL per injection (approximately 4 -6 injections), and administered as spatially divided intradermal injections in the same extremity to increase volume distribution and enhance antigen presentation to lymph node regions shared with the urinary bladder. Dosing wil l rotate injection site extremities every four timepoints: antero -lateral left thigh, antero -lateral right thigh, left buttock , and right buttock. If injection site reactions are reported as an AE, an alternative injection site may be used upon discussion with the sponsor. Vesigenurtacel -L: Derived from irradiated urothelial bladder cancer cells expressing HLA - A1 on at least 70% of the cells, producing ≥ 60 ng of gp96 -Ig/24h per 1 x 106 cells with ≥ 70% viability by trypan blue exclusion. Vesigenurtacel -L is provided as single -dose vials either 1) as concentrated frozen liquid, which will require dilution by the pharmacy with sterile saline , or 2) as fully -diluted frozen liquid not requiring additional dilution. In either case the final dr ug product will consist of cells resuspended in buffered saline containing human serum albumin (HSA), dimethyl sulfoxide ( DMSO ), and pentastarch and will be delivered at doses of either 1 x 106 cells or 1 x 107 cells. Placebo: 0.15% Intralipid solution in freezing solution (buffered saline, HSA, DMSO and pentastarch) without vesigenurtacel -L cells. BCG: Intravesical administration according to the institution’s practice Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 9 of 86 Eligibility criteria: Inclusion Criteria: 1. Willing and able to sign informed consent and comply with the protocol , including clinic visits to receive weekly vesigenurtacel -L injections for 12 doses followed by either monthly vesigenurtacel -L injections for three months in Phase 1 or three courses of three once -weekly injections in Phase 2 . 2. Histologically or cytologically confirmed non -muscle invasive bladder cancer [Ta, T1 or Tis (CIS)] . Papillary disease must have been removed by transurethral resection or fulguration . 3. Either i. High-risk disease, defined as T1 and/or high-grade and/or CIS , or ii. Intermediate -risk disease defined as Ta low -grade with at least three of the following four risk factors: multiple tumors, tumor size > 3cm, early recurrence (<1 year from previous staging procedure ), or recurrence with a frequency of more than once in any 12 month period 4. Patients must be BCG naïve or have completed previous BCG treatment >12 months prior to the baseline staging procedure . 5. For Phase 2 only: Arms 1, 2 , and 3: Suitable , in the opinion of the investigator, to receive a 6-week course of induction intravesical BCG in the adjuvant setting within 6 weeks following the baseline staging procedure for the current occurrence of non -muscle invasive bladder cancer . Arm 4: Suitable for monotherapy vaccine administration post - TURBT. For Phase 1 only: Has previously received 3 -6 weekly doses of BCG . 6.