Dr. Nissola is an award-winning researcher with a diverse and unique spectrum of experiences in medicine. He has worked in clinical care in impoverished communities on the outskirts of South America, has led medical affairs teams with multi-billion dollar drug assets, and has conducted innovative drug discovery early phase clinical trials with leading academic institutions in the United States. Those experiences provide him with an unparalleled perspective in life sciences.
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 designed, authored and 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.
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.
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
Dr. Leo Nissola, while at The Parker Institute for Cancer Immunotherapy, designed, authored, and conducted this clinical trial. In the United States, prostate cancer remains the second leading cause of cancer-related mortality among men. While the 5-year survival rate for prostate cancer in its early stages is very high, nearly one-third of cases will recur and progress to metastatic disease. The 5-year survival rate drops to about 30% for these patients.
The standard treatment for prostate cancer reduces levels of the hormones responsible for cancer growth. The treatment is typically effective in the short term; however, despite hormone-based therapy, metastatic prostate cancer will eventually continue to grow and spread, transforming into metastatic castration-resistant prostate cancer (mCRPC). This study aims to determine how to defeat this advanced disease.
This study aims to test a variety of treatment combinations designed by prostate cancer specialists from across the globe to combat this difficult-to-treat advanced prostate cancer subtype.
Dr. Nissola employed a "platform" or "master protocol" design that is exploratory for allow more speed, agility while observing health and safety data. This relatively new type of trial design allows the inclusion of new treatment combinations as the trial progresses in order to advance scientific discovery more rapidly and efficiently.
With the platform design, researchers are able to build on new data and test promising new therapies within the same study, as opposed to initiating a new study. It can reduce the number of administrative steps required to initiate a study, thereby increasing productivity and accelerating the development of new therapies to benefit patients.
Multiple groups of patients will be treated with various therapeutic combinations. The number of patient groups and combinations will increase over time.
The following treatment combinations were included in the initial clinical development plans:
As the Clinical lead and Lead Clinical Scientist for this study, Dr. Nissola recruited patients from the following academic institutions:
Partners for this study included:
For more information on this trial (NCT03835533), visit www.clinicaltrials.gov.
Patient Population: Metastatic Castration-Resistant Prostate Cancer Patients After Secondary Androgen Receptor Signaling Inhibitor Deprivation Therapy (e.g., abiraterone, enzalutamide, apalutamide).
Please click here for the full study.
Immune-mediated adverse events (imAE) commonly occur in patients treated with immune checkpoint inhibitors (ICI), and pneumonitis is known to occur in 3 -5 % of patients treated with anti-PD-1 / PD-L1 antibodies.1 Most cases are grade 1 or 2 events and can be treated with immunosuppression, but high-grade events occur in a minority of patients and can be fatal.2 Since lung inflammatory phenotypes, including fibrotic idiopathic interstitial pneumonias and infectious pneumonias, were associated with allelic variation in Human Leukocyte Antigen (HLA) genes,3 4 we hypothesized that HLA variants might also be a risk factor for ICI- associated pneumonitis.
Out of 1761 atezolizumab (anti-PD-L1) treated patients across nine Genentech (GNE) clinical trials with available whole-genome sequencing data, 72 (4.1%) developed pneumonitis (table 1). We inferred HLA genotypes using HLA-HD5 and performed an association study including 87 alleles with a carrier frequency of >2%. In order to confirm our results, and to test whether the association is generalizable to different classes of ICI, we genotyped two additional cohorts using an Illumina genome-wide SNP array (GSA v3), followed by HLA imputation using HIBAG6: (1) 20 ICI-treated cancer patients with pneumonitis and 20 matched controls without from a pilot study on the AEROSMITH trial from Parker Institute for Cancer Immunotherapy (PICI); (2) 15 ICI-treated melanoma patients with pneumonitis and 149 without from Peter MacCallum Cancer Centre (PMC) (table 1).
Two HLA class II alleles that are part of a common haplotype showed significant associations with pneumonitis risk after multiple testing adjustment (HLA-DRB1*15:01, HLA-DQA1*01:02), with HLA-DRB1*15:01 showing the strongest association (p = 0.0002, odds ratio (OR) =2.51). No associations were identified in the control arms (N = 1192). In the PICI pilot cohort, HLA-DRB1*15:01 did not reach statistical significance in spite of a comparable OR (p = 0.26, OR = 2.75), but the allele was significantly associated with pneumonitis risk in the PMC cohort (p = 0.03, OR = 3.92). A meta-analysis across the three cohorts yielded a highly significant p-value of 1.2x10–5 (OR = 2.67, figure 1), suggesting that the association is generalizable across ICI. Importantly, the same class II haplotype was previously shown to be associated with diverse lung inflammatory, including fibrotic, phenotypes.
In summary, our findings establish HLA class II allelic variation as a potential risk factor in ICI-associated pneumonitis, and future research is warranted to determine whether this genetic association can be refined according to specific clinical presentations.
Dr. Nissola has medical affairs teams and multi-billion-dollar drug assets at leading biotechnology and multinational pharmaceutical companies.
Dr. Nissola has collaborated with the brightest minds in medicine in the United States and abroad for the past eight years. He has collaborated with major pharmaceutical and biotech firms to shape their medical affairs functions and disseminate crucial new scientific findings. Medical affairs are becoming increasingly important to the success of drug assets and to relationship building. His extensive knowledge of medical affairs—serving clients in South America, Europe, and the United States—makes him uniquely qualified to lead and collaborate on cross-industry initiatives, thereby enabling the medical affairs function to realize its potential to enhance patient outcomes and experiences.
He focuses specifically on the following areas:
Innovating evidence generation – Leading rapid-cycle, integrated evidence generation across HEOR, RWE, Phase IIIb/IV, and all other data, supported by microanalysis to tailor information to the needs of individual patients and improve the lives of patients throughout the product life cycle.
Dr. Nissola has assisted biotech, pharmaceutical, and investor executives, founders, and investors over the years in bringing and incorporating new cutting-edge technology. Obtaining expert insight early on life sciences and health technology projects can prevent and resolve unanticipated issues later on.
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