Clinical Research, Drug Development, Medical Affairs

Dr. Nissola has taken impossible ideas and thought-provoking breakthrough science into clinical development plans and clinical trial protocols—leading complex, adaptive, multi-stage, and platform studies for oncology and immunotherapy. His studies evaluated human health, clinical data, and the safety risks associated with drugs, devices, and biological materials.

Dr. Nissola conducted Phase I and II clinical programs evaluating experimental treatments, including novel drug combinations, molecules, DNA-based vaccines, and analyzed tumor responses to immune checkpoint inhibitors in cancer patients in leading academic institutions in the United States.

Clinical Trials

This is an open-label, exploratory study to evaluate nivolumab with or without ipilimumab based on the percentage of tumoral CD8 cells at the time of treatment in participants with varying advanced solid tumors. Participants who have a tumor with ≥ 15% CD8 cells (classified as CD8 high) will receive nivolumab monotherapy, and participants who have a tumor with < 15% CD8 cells (classified as CD8 low) will receive ipilimumab in combination with nivolumab.The aim of this study is to provide a prospective classification of CD8 high (immunologically "hot") versus CD8 low (immunologically "cold") tumors at the time of treatment, based on the percentage of CD8 cells in a tumor biopsy, and to address the predictive value of the CD8 biomarker for selecting patients for treatment with nivolumab with or without ipilimumab.

A total of up to approximately 200 participants with advanced metastatic cancer will be enrolled. Ongoing monitoring for safety and futility will be implemented based on the method of Thall and colleagues (Thall et al, 1995) separately in the CD8 high and CD8 low tumor groups. Single-agent nivolumab will be administered at 360 mg intravenously (IV) every 3 weeks (Q3W). Participants who continue to show clinical benefit after the first disease assessment will receive nivolumab 480 mg IV every 4 weeks (Q4W) until progressive disease (PD) or intolerable toxicity.

At PD, participants will be allowed to add ipilimumab. For nivolumab and ipilimumab combination therapy, nivolumab will be administered at 360 mg IV Q3W, and ipilimumab will be administered at 1 mg/kg IV Q3W for the first 2 doses and then every 6 weeks for the 3rd and 4th doses, followed by nivolumab 480 mg IV Q4W until PD or intolerable toxicity. After receipt of the first dose of ipilimumab, the Investigator may determine (based on clinical symptoms) the number of future doses of ipilimumab the participant will receive, for a maximum of 4 doses.

Participants who stop ipilimumab dosing early due to toxicities, may start nivolumab maintenance (ie, 4 doses [12 weeks] of nivolumab following the first dose).Advanced prostate cancer participants with tumoral CD8 ≥ 15% will be enrolled in the nivolumab monotherapy arm. A total of approximately 20 participants with Advanced Prostate Cancer and tumoral CD8 < 15% will be randomly allocated to 1 of 2 cohorts using combinations of ipilimumab and nivolumab.

Clinical Trials

Intermittent Androgen Deprivation (ADT) is an acceptable treatment option in M0HNPC with no significant survival difference and improved quality of life versus (vs) continuous. AA improves survival in metastatic HNPC.

We hypothesize that AA added to intermittent ADT will improve outcome without delaying testosterone (T) recovery.Patients (Pts) with PSA recurrent, after definitive local treatment, M0HNPC were randomized 1:1 to 8 month AA(1g/qd)+ prednisone (5mg /qd)+LHRHa vs LHRHa.

Pts were eligible to cross over upon progression We primarily studied difference in PSA free survival. Secondary endpoints included time to T recovery, safety and associations with clinical/tumor characteristics. Sample size had 93% power to detect 1 year post treatment PSA free survival difference of 20 %. Stratification factors were radical prostatectomy (RPS) vs radiation (EBRT), PSA ≥ vs < 10, time to recurrence ≥ vs < 3yrs. Rising PSA of 0.2 confirmed by subsequent > 0.2 required after RPS and nadir PSA +2 for prior EBRT.197 of 200 randomized pts were treated (99 AA+LHRHa /98 LHRHa).

Median age was 65 (range 42- 85), Performance Status 0, PSA 1 (0.3-33.3 ng/ml), T 346 (160-946 ng/dL). 186 (94%) had undergone RPS. 128 (65 %) had PSA relapse by Jan/18. Pts on 8 month AA+LHRHa had median PSA free survival 28.3 months (range 24.2—35.4) vs 21.1 (19.1-27.2) for LHRHa pts. (HR 0.62; 95 % Confidence Interval 0.44-0.88; p 0.007).

Median time to T recovery for AA+LHRHa was 13.1 ms vs 12.9 for LHRHa. AA+LHRHa treatment outcome was favorable regardless of pretreatment PSA, Gleason Score, pathology, time to relapse from treatment, definitive treatment type, including if RPS +EBRT (57%).

No Grade 4 adverse events (AE) or new safety concerns reported. Grade 3 AEs: arterial hypertension 6 (5 AA+LHRHa arm), liver function test elevation 4 (AA+LHRHa arm). Most common AEs were Grade 1 hot flashes (71%) and fatigue (51%) with no difference between arms.

Findings support that 8 month treatment with Abiraterone Acetate plus LHRHa in M0HNPC improves PSA free survival compared to LHRHa without delay in testosterone recovery or significant safety concerns. Clinical trial information: NCT01786265

Platform Study

Nissola, L., et al.

First-ever Immunotherapy Platform Study for Prostate Cancer Patients.

First Platform Study of The Parker Institute for Cancer Immunotherapy.

A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and Immunotherapy Combinations for the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer -NCT03835533This is an open-label, non-randomized, exploratory platform protocol designed to assess the safety and antitumor activity of multiple immunotherapy combinations in participants with mCRPC who have received prior therapy.

The platform study will consist of 2 stages: Stage 1, an initial stage to evaluate safety, biomarkers, and clinical activity of a combination and Stage 2, an expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results from Stage 1.

The Sponsor intends to modify and/or add new combinations to the protocol as data emerge from this and other trials.Participants must provide consent for archival tissue from a prior biopsy or surgery for prostate cancer and must consent to baseline and on-treatment biopsies, if medically feasible. Participants will be assigned to receive one of the enrolling combination study interventions and will be monitored for safety and response.

Cohort A: NKTR-214 + Nivolumab
Cohort B: Nivolumab + CDX-301 (FL3 ligand) + Poly-ICLC + Stereotactic Body Radiation Therapy
Cohort C: Nivolumab + Poly-ICLC + INO-5151 (DNA-based cancer vaccine, PSA and PSMA plasmids + DNAvector expressing interleukin 12)+ Electroporation with Cellectra 2000.

Clinical Trials

Patient Population: Metastatic Castration-Resistant Prostate Cancer Patients After Secondary Androgen Receptor Signaling Inhibitor Deprivation Therapy (e.g., abiraterone, enzalutamide, apalutamide).

Clinical Research

Allelic variation in Human Leukocyte Antigen class II genes is associated with pneumonitis risk in cancer patients treated with immune checkpoint inhibitors.
Immunotherapy Toxicities. Presented at Hall at the Walter E. Washington Convention Center, Washington, D.C.

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