All Drugs and Chemicals

Vaccines

The schedule for vaccination will be weeks 1, 5, 9, 13, 17, and 21. All vaccines will occur within +/- 1 week with at least 3 weeks between vaccines.

Neoantigen DNA Vaccine

* Ichor Medical Systems
* All study injections will be given intramuscularly using an integrated electroporation device

Integrated electroporation device

William E Gillanders, M.D.

This is an expanded access use study. Safety data will be collected from participants.

Expanded Access Neoantigen Vaccine in Solid Tumors

Washington University School of Medicine

Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Carcinoma

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Durvalumab

Immunoglobulins

Antineoplastic Agents, Immunological

* The first neoantigen DNA vaccine injection will take place following the completion of standard of care therapy. The day of the first vaccine injection will be referred to as Day 1
* The schedule of vaccination is Day 1, Day 29 ± 7, Day 57 ± 7, Day 85 ± 7, Day 113 ± 7, and Day 141 ± 7 with at least 21 days between injection days
* For patients who are randomized to the neoantigen DNA vaccine plus durvalumab arm, the neoantigen-specific T cell response will be assessed prior to Day 85. If a neoantigen-specific T cell response is present, durvalumab will be started on Day 85, and will be administered Q4W at a dose of 1500 mg over the course of 60 minutes. If a neoantigen-specific T cell response is not present, these patients will be replaced but may continue to receive the neoantigen DNA vaccine on study. They will not be transferred to the vaccine-only arm.

* The first neoantigen DNA vaccine injection will take place following the completion of standard of care therapy. The day of the first vaccine injection will be referred to as Day 1
* The schedule of vaccination is Day 1, Day 29 ± 7, Day 57 ± 7, Day 85 ± 7, Day 113 ± 7, and Day 141 ± 7 with at least 21 days between injection days

-The vaccine will be given by the TDS-IM system

Neoantigen DNA vaccine

-At each vaccination time point, patients will receive two injections at separate sites.

TDS-IM system (Inchor Medical Systems)

-Baseline, following completion of standard of care therapy, Day 1, Day 57, Day 113, Day 159, and 1 year after initiation of neoantigen DNA vaccine therapy

Peripheral blood draw

William Gillanders, M.D.

This is a single institution, open-label randomized phase 1 trial of neoantigen DNA vaccine alone vs. neoantigen DNA vaccine plus durvalumab in triple negative breast cancer (TNBC) patients following standard of care therapy. Patients with newly diagnosed clinical stage II-III TNBC are eligible for enrollment. Patients will receive standard of care therapy including chemotherapy, surgery and radiation therapy as clinically indicated. Following standard of care therapy, patients will be randomized to receive either a neoantigen DNA vaccine alone, or a neoantigen DNA vaccine + durvalumab.

Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy

A Randomized Phase 1 Trial of Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy

* Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
* Assessment of the safety of neoantigen DNA vaccines will include both clinical observation and laboratory evaluation. Safety will be closely monitored after injection with eight or more clinical and laboratory assessments in the first 24 weeks of the trial

-Peripheral blood will be collected at multiple time points before and after vaccination

The ELISpot assay was performed after in vitro culture of patient PBMC with neoantigen peptide for \~12 days. The number of spot-forming T cells, a surrogate for the number of neoantigen-specific T cells, was determined after neoantigen peptide re-stimulation for the duration of the assay (48 hours) and compared to that of control cells that were not re-stimulated with neoantigen during the assay. One-way anova analysis was performed on replicate assessments.

Multiparametric flow cytometry was performed as a second readout to assess neoantigen-specific T cell reactivity. Markers included CD4, CD8, IFNγ, and a viability marker. After culture, as described above, T cells were stimulated for 6 hours with/without neoantigen and stained with fluorescent antibodies specific for the various markers. Data were analyzed by comparing the percentage IFNγ+ CD4/CD8 cells between neoantigen-stimulated vs unstimulated T cells; a \>2-fold increase in percentage positive cells after neoantigen stimulation was considered positive.

MedImmune LLC

National Cancer Institute (NCI)

National Institutes of Health (NIH)

Neoantigen DNA Vaccine + Durvalumab

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Williams Gillanders, M.D.

Grade 1-2 anemia

Grade 1-2 chest pain-cardiac

Grade 1-2 palpitations

Grade 1-2 hypothyroidism

Grade 1-2 visual migraine

Grade 1-2 abdominal cramps

Grade 1-2 constipation

Grade 1-2 diarrhea

Grade 1-2 dyspepsia

Grade 1-2 gastritis

Grade 1-2 nausea

Grade 1-2 vomiting

Grade 1-2 ankle edema

Grade 1-2 chills

Grade 1-2 edema limbs

Grade 1-2 fatigue

Grade 1-2 fever

Grade 1-2 flu-like symptoms

Grade 1-2 injection site pain

Grade 1-2 localized edema

Grade 1-2 neck edema

Grade 1-2 COVID-19 infection

Grade 1-2 infection from cat bite

Grade 1-2 oral herpes lesions

Grade 1-2 port infection

Grade 1-2 upper respiratory infection

Grade 1-2 urinary tract infection

Grade 1-2 wound infection

Grade 1-2 broken foot

Grade 1-2 bruising

Grade 1-2 fall

Grade 1-2 spinal fracture

Grade 3-5 vascular access complication

Grade 1-2 alanine aminotransferase increased

Grade 1-2 lymphocyte count decreased

Grade 3-5 lymphocyte count decreased

Grade 1-2 neutrophil count decreased

Grade 1-2 weight gain

Grade 1-2 weight loss

Grade 1-2 white blood cell decreased

Grade 1-2 anorexia

Grade 1-2 hyperglycemia

Grade 1-2 hyperkalemia

Grade 1-2 hypokalemia

Grade 1-2 hyponatremia

Grade 1-2 arthralgia

Grade 1-2 bone pain

Grade 1-2 myalgia

Grade 1-2 neck pain

Grade 1-2 pain in extremity

Grade 1-2 dizziness

Grade 1-2 headache

Grade 1-2 neuralgia

Grade 1-2 peripheral sensory neuropathy

Grade 1-2 insomnia

Grade 1-2 breast pain

Grade 1-2 vaginal dryness

Grade 1-2 allergic rhinitis

Grade 1-2 chest congestion

Grade 1-2 cough

Grade 1-2 dyspnea

Grade 1-2 rhinorrhea

Grade 1-2 sore throat

Grade 1-2 blanching of fingers on left hand

Grade 1-2 candidal rash

Grade 1-2 eczema

Grade 1-2 nail changes

Grade 1-2 nodule on breast

Grade 1-2 rash maculo-papular

Grade 1-2 skin hyperpigmentation

Grade 1-2 bilateral breast fat grafting

Grade 1-2 hypertension

Grade 1-2 lymphedema

Safety of Neoantigen DNA Vaccines Given Alone or in Combination With Durvalumab as Measured by Number of Adverse Events Experienced by Patient

The luminex assay was not able to be performed.

Immune Response to Neoantigen DNA Vaccines Given Alone or in Combination With Durvalumab as Measured by Luminex Assay

4 participants in the Neoantigen DNA vaccine + Durvalumab arm were not evaluable due to early withdrawal from treatment (2=lack of efficacy, 2=withdrawal by subject). 2 participants in the Neoantigen DNA vaccine arm were not evaluable due to early withdrawal from treatment (1=adverse event, 1=only 5 out of 6 vaccines received).

Number of Participants With an Immune Response to Neoantigen DNA Vaccines Given Alone or in Combination With Durvalumab as Measured by Interferon-gamma ELISPOT Assay

Number of Participants With Immune Response to Neoantigen DNA Vaccines Given Alone or in Combination With Durvalumab as Measured by Multiparametric Flow Cytometry - CD4

Number of Participants With Immune Response to Neoantigen DNA Vaccines Given Alone or in Combination With Durvalumab as Measured by Multiparametric Flow Cytometry - CD8

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Lung Neoplasms

Small Cell Lung Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Carboplatin

Etoposide

Etoposide phosphate

* Patients will receive durvalumab (1500mg Q3W) in combination with standard of care carboplatin and etoposide for a total of 4 cycles given every 3 weeks
* Beginning 4 weeks following Cycle 4 of carboplatin/etoposide/durvalumab, patients on will then receive 6 cycles of durvalumab 1500 mg with the polyepitope neoantigen DNA vaccine, both administered once every 4 weeks
* Patients may then receive durvalumab every 4 weeks until disease progression or drug toxicity
* Should a delay in vaccine preparation occur, patients will begin durvalumab and the vaccine will be added with the subsequent cycle.

All study injections will be given intramuscularly using an integrated electroporation device (TDS-IM system, PapiVax Biotech). At each vaccination time point, patients will receive two injections of the neoantigen DNA vaccine, one injection into each deltoid or lateralis.

-Integrated electroporation administration system

TDS-IM v2.0 Device

-Pre-treatment, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Vaccine Day 1, Vaccine Day 29, Vaccine Day 85, Vaccine Day 141, on even numbers of cycles for durvalumab for one year following completion of vaccine

Peripheral blood draws

Jeffrey Ward, M.D., Ph.D.

Ramaswamy Govindan, M.D.

Saiama Waqar, M.D.

Daniel Morgensztern, M.D.

Maria Baggstrom, M.D.

The investigators hypothesize that a personalized neoantigen vaccine combined with durvalumab will improve the progression free survival of patients with extensive state small cell lung cancer (ES-SCLC).

Personalized Neoantigen Vaccine in Combination With Durvalumab (MEDI4736) in Extensive Stage Small Cell Lung Cancer

Phase II Study of a Personalized Neoantigen Vaccine in Combination With Durvalumab (MEDI4736) in Extensive Stage Small Cell Lung Cancer

All study data will be shared with the study sponsor and will be available from presentations and upon publication.

-Safety and tolerability will be measured by National Cancer Institute Common Terminology Criteria (NCI CTCAE) v 5.0

-Feasibility is defined as the ability to produce a vaccine for 80% of patients enrolled

* PFS is defined as the duration of time from start of durvalumab to time of progression or death, whichever occurs first.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

-The response conversion rate is defined as the proportion of patients who improve in RECIST v1.1 category subsequent to vaccination.

-The duration of response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

-Defined as time from start of durvalumab to death due to any causes

AstraZeneca

Gateway for Cancer Research

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Prostatic Neoplasms

Hypersensitivity

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Anti-Infective Agents

Metronidazole

Hormones

Nivolumab

Ipilimumab

Immune Checkpoint Inhibitors

* Within 60 days after the last chemo, patients will start a priming dose of PROSTVAC-V, and subsequent doses of PROSTVAC- F (weeks 0, 2, 5, 8, 11, 14, and 17). During "Treatment A" phase, subjects should receive nivolumab intravenously on Day 1 of each cycle every 3 weeks for 6 doses. Ipilimumab on Day 1 of each cycle every 3 weeks for 2 doses.
* Patients will then receive a neoantigen DNA vaccine with continuous nivolumab treatment. The vaccine will be administered starting approximately week 21 by intramuscular injection for a total of 6 treatments every 28 days +/-7 days. Each DNA vaccination will be 4 mg vaccine administered intramuscularly using a TriGrid electroporation device. Patients will receive nivolumab at 480 mg every 28 days concurrently with neoantigen DNA vaccine. This is Treatment B. In the event the DNA vaccine production is delayed, patients will receive single agent nivolumab every 4 weeks beginning week 21 until the vaccine is ready

-Replication-competent vaccinia virus which has been engineered to encode the sequences for a modified human prostate-specific antigen (PSA) and a triad of co-stimulatory molecules (TRICOM)

PROSTVAC-V

-Fowlpox virus which does not replicate in human cells and has been engineered to encode the same sequences present in PROSTVAC-V.

PROSTVAC-F

-Nivolumab is a human monoclonal antibody (mAb)

-Ipilimumab is a mAb blocking the inhibitory signal mediated by cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4), a protein receptor that downregulates the immune system.

Each DNA vaccination will be 1 mL vaccine administered intramuscularly. At each vaccination time point, patients will receive two injections at separate sites.

TriGrid Delivery System

-Pre-treatment, post-treatment A (optional), and end of treatment

Tumor biopsy

-At the time of pre-treatment biopsy, mid-treatment of chemo-ADT, at time of enrollment (prior to POSTVAC administration), mid-treatment A, mid-treatment B (multiple)

Peripheral blood

-Post chemo/pre-treatment A, post-treatment A, pre-treatment B, post-treatment B

Fecal samples

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Expanded Access Neoantigen Vaccine in Solid Tumors	NCT03914872	Solid Tumor, Ad...	Neoantigen DNA ... Integrated elec...	18 Years -	Washington University School of Medicine
Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy	NCT03199040	Triple Negative... Triple Negative... TNBC - Triple-N... Triple-negative...	Durvalumab Neoantigen DNA ... TDS-IM system (... Peripheral bloo...	18 Years -	Washington University School of Medicine
Expanded Access Neoantigen Vaccine in Solid Tumors	NCT03914872	Solid Tumor, Ad...	Neoantigen DNA ... Integrated elec...	18 Years -	Washington University School of Medicine
Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy	NCT03199040	Triple Negative... Triple Negative... TNBC - Triple-N... Triple-negative...	Durvalumab Neoantigen DNA ... TDS-IM system (... Peripheral bloo...	18 Years -	Washington University School of Medicine
Neoantigen DNA Vaccine Alone vs. Neoantigen DNA Vaccine Plus Durvalumab in Triple Negative Breast Cancer Patients Following Standard of Care Therapy	NCT03199040	Triple Negative... Triple Negative... TNBC - Triple-N... Triple-negative...	Durvalumab Neoantigen DNA ... TDS-IM system (... Peripheral bloo...	18 Years -	Washington University School of Medicine
Personalized Neoantigen Vaccine in Combination With Durvalumab (MEDI4736) in Extensive Stage Small Cell Lung Cancer	NCT04397003	Extensive-stage...	Neoantigen DNA ... Durvalumab TDS-IM v2.0 Dev... Peripheral bloo...	18 Years -	Washington University School of Medicine
Personalized Neoantigen Vaccine in Combination With Durvalumab (MEDI4736) in Extensive Stage Small Cell Lung Cancer	NCT04397003	Extensive-stage...	Neoantigen DNA ... Durvalumab TDS-IM v2.0 Dev... Peripheral bloo...	18 Years -	Washington University School of Medicine
Neoantigen DNA Vaccine in Combination With Nivolumab/Ipilimumab and PROSTVAC in Metastatic Hormone-Sensitive Prostate Cancer	NCT03532217	Metastatic Horm...	PROSTVAC-V PROSTVAC-F Nivolumab Ipilimumab Neoantigen DNA ... TriGrid Deliver... Tumor biopsy Peripheral bloo... Fecal samples Leukapheresis	18 Years -	Washington University School of Medicine

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