On February 14, 2022 Children’s Hospital Los Angeles reported A new study independently verified the value of a system that assesses hepatoblastoma risk in children (Press release, Children’s Hospital Los Angeles, FEB 14, 2022, View Source [SID1234608105]). Hepatoblastoma is a rare childhood liver cancer, usually seen within the first three years of a child’s life with 50 to 70 cases occurring in the U.S. each year. The researchers also discovered the potential for tumor histology—the examination of a tumor’s tissue and its structure—to predict a patient’s hepatoblastoma prognosis.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Leo Mascarenhas, MD, MS, Deputy Director of the Cancer and Blood Disease Institute, co-led the study with Shengmei Zhou, MD, a pediatric pathologist and diagnostician at CHLA. The findings are published in JAMA Network Open.

Risk stratification for hepatoblastoma

The risk assessment process, called risk stratification, has the potential to improve success rates for children undergoing hepatoblastoma treatment. Risk stratification can also reduce unnecessary exposure to chemotherapy. Often, treatment for low-risk cases is too aggressive, or liver transplants are not prioritized for high-risk cases.

In 2016, leading hepatoblastoma researchers from around the world created the Children’s Hepatic tumors International Collaboration Hepatoblastoma Stratification (CHIC-HS). Information such as age at diagnosis, whether the tumor has spread within the body and alpha fetoprotein level (which is usually increased in liver cancer) contributes to the CHIC-HS risk categorization. This database of clinical trial data aims to establish a common approach to staging and risk stratification. The CHIC-HS system has yet to be globally adopted, however, due to a lack of validation.

"Independent validation is valuable for others to use this risk stratification," emphasizes first author Dr. Zhou. "It gives them confidence."

Validating the CHIC-HS system

The study retrospectively tested the CHIC-HS system on an independent cohort of patients diagnosed and treated at Children’s Hospital Los Angeles from 2000 to 2016. The team examined the electronic medical records, imaging and pathology of 96 patients.

The investigators confirmed that the CHIC-HS system successfully predicts how much risk a tumor poses. Children in the lower-risk categories improved with minimal treatment. Those in higher-risk groups required a more intense treatment approach.

The CHIC-HS system also corresponded with long-term patient outcomes after treatment. These outcomes include overall survival, and how long a patient lives without relapse or cancer progression.

For 84 of the patients included in the study, tumor histology collected before treatment was available for analysis. Pretreatment biopsies, which provide tissue samples of the tumor, are not always possible or commonly collected. Having a cohort of this size offered a unique opportunity to assess the relationship between histological characteristics in the tumor, risk category and patient survival.

The investigators discovered that certain histological features predicted patient risk and long-term outcomes, including relapse and survival rates. "Histology may help further enhance the risk stratification scale," concludes Dr. Mascarenhas. "Our hope is that our work will be proven in the ongoing Pediatric Hepatic International Tumor Trial." (NCT03533582, North America; NCT03017326, Europe).

Ongoing research at CHLA focuses on the identification of genetic markers that may further contribute to risk stratification and inform hepatoblastoma treatment.

"This cancer, from being a pretty deadly cancer, is now highly curable in a lot of patients," says Dr. Mascarenhas. "A lot of our goals should really be aimed at limiting the toxicity of treatment in these patients and, for those with high-risk disease, figuring out how to improve their outcomes."

Additional authors of the paper include: Jemily Malvar, MS, of Children’s Hospital Los Angeles and Yueh-Yun Chi, PhD, James Stein, MD, Larry Wang, MD, PhD, Yuri Genyk, MD, and Richard Sposto, PhD, of Children’s Hospital Los Angeles and the Keck School of Medicine at USC.

This research was funded in part by grants UL1TR001855 from the National Center for Advancing Translational Science and 5P30CA014089-44 from the National Cancer Institute of the U.S. National Institutes of Health. The research also received support from the Society for Pediatric Pathology Young Investigator Research Grant and the Names Family Foundation.

On February 14, 2022 BioDuro-Sundia, a leading drug discovery, development and commercial services organization backed by Advent International, reported the appointment of Kent M. Payne, PhD, as Chief Executive Officer (Press release, Bioduro-Sundia, FEB 14, 2022, View Source [SID1234611016]). He originally joined BioDuro-Sundia in 2019 as President, Global CMC Solutions.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"For the past 2+ years Kent has distinguished himself, setting a vision for growth, building strong teams and processes to execute that growth most recently as Corporate Head of Transition," said David Preston, Chairman of the Board, BioDuro-Sundia. "Under his leadership, we have generated record growth across all business units. The Board has full confidence and is excited to have him formally lead our next phase of growth with planned expansions in nearly every aspect of our China and US operation."

The executive team, led by Payne, will continue to be co-located in China and the US, providing balance for the global contract research, development and manufacturing organization (CRDMO) for both drug substance and drug product.

"I am honored to serve as CEO at this time of remarkable growth; we will be adding 1,000 people to our company in 2022 alone and bringing on board new capacities at every facility, including discovery, development and manufacturing," said Kent M. Payne, Ph.D., CEO.

"With support from Advent International, we are making the needed investment into our teams, systems and processes to make sure we deliver ‘right first time’, stay fast and flexible, and maintain our customer focus culture. This is our promise to each and every client, and to the patients awaiting new life-saving medicines."

On February 14, 2022 AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that positive results from the Phase 3 PROpel trial showed LYNPARZA in combination with abiraterone plus prednisone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) versus abiraterone plus prednisone, a standard of care, as a first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations (Press release, Merck & Co, FEB 14, 2022, View Source [SID1234608069]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Results from the trial will be presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (GU) Cancers Symposium on Feb. 17, 2022 (Abstract 11).

Globally, prostate cancer is the second most common cancer in patients assigned as male at birth, with an estimated 1.4 million patients diagnosed worldwide in 2020. Approximately 10-20% of men with advanced prostate cancer are estimated to develop CRPC within five years, and at least 84% of these men may develop metastases at the time of CRPC diagnosis. Patients with advanced prostate cancer have a particularly poor prognosis, and the five-year survival rate remains low.

PROpel is a randomized, double-blind, multi-center Phase 3 trial. In Sept. 2021, at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS. LYNPARZA in combination with abiraterone plus prednisone (n=399) reduced the risk of disease progression or death by 34% (HR=0.66 [95% CI, 0.54-0.81]; p<0.0001) versus abiraterone plus prednisone and placebo (n=397) in patients with mCRPC regardless of HRR gene mutation status. Median rPFS was 24.8 months for LYNPARZA combined with abiraterone versus 16.6 months for abiraterone, an improvement of more than eight months.

The most common adverse events (AEs) (≥20%) for LYNPARZA plus abiraterone were anemia (46%), fatigue (37%) and nausea (28%). Grade ≥3 AEs were anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (2%), decreased appetite (1%), vomiting (1%), back pain (1%), diarrhea (1%) and nausea (0.3%). Approximately 14% of patients who received LYNPARZA in combination with abiraterone discontinued treatment due to an AE. Health-related quality of life, an exploratory endpoint, was measured longitudinally using Functional Assessment of Cancer Therapy-Prostate (FACT-P), a patient reported outcome instrument. No detriment to quality of life was found between the two study arms.

At this interim analysis, PROpel also showed a trend towards improved overall survival (OS) for LYNPARZA combined with abiraterone plus prednisone versus abiraterone plus prednisone and placebo; however, the difference did not reach statistical significance at the time of this data cut-off (analysis at 29% data maturity) (HR=0.86 [95% CI, 0.66-1.12]; p<0.29). The trial will continue to assess OS as a key secondary endpoint.

Fred Saad, professor and chairman of Urology and director of Genitourinary Oncology at the University of Montreal Hospital Center and principal investigator in the trial, said, "It is clear to me that the prognosis for metastatic castration-resistant prostate cancer is extremely poor, and many patients are able to receive only one line of effective therapy. The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression versus abiraterone by more than eight months, demonstrate the potential for this combination to become a new standard of care option in metastatic castration-resistant prostate cancer, if approved."

Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, "This LYNPARZA combination has the potential to afford first-line patients more time without disease progression while also maintaining their quality of life. The PROpel results are impressive because active comparator trials set a high bar and, in this trial, LYNPARZA plus abiraterone showed a significant clinical improvement when compared to an active standard of care in patients with metastatic castration-resistant prostate cancer, regardless of whether they have an HRR gene mutation."

Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "Results from the PROpel trial showed that LYNPARZA in combination with abiraterone plus prednisone reduced the risk of disease progression or death by a third compared to abiraterone plus prednisone in the first-line setting for patients with metastatic castration-resistant prostate cancer, regardless of their biomarker status. We look forward to discussing these important results with global health authorities as quickly as possible. We thank the patients, caregivers and health care providers for participating in this study."

Summary of PROpel Results

LYNPARZA + abiraterone

(n=399)

Placebo + abiraterone

(n=397)

rPFS by Investigator1

Number of patients with events (%)

168 (42)

226 (57)

Median PFS (months)

24.8

16.6

HR (95% CI)

p-value

0.66 (0.54, 0.81)

<0.0001

rPFS by BICR2

Number of patients with events (%)

157 (39)

218 (55)

Median PFS (95% CI) (months)

27.6

16.4

HR (95% CI)

p-value (nominal)

0.61 (0.49, 0.74)

<0.0001

OS3

Number of patients with events (%)

107 (27)

121 (31)

Median OS (95% CI) (months)

NR4

NR

HR (95% CI)

p-value

0.86 (0.66, 1.12)

0.29

Time to second progression or death (PFS2)

Number of patients with events (%)

70 (18)

94 (24)

Median (months)

NR

NR

HR (95% CI)

p-value

0.69 (0.51, 0.94)

0.0184 (nominal)

Time to first subsequent anti-cancer therapy or death (TFST)

Number of patients with events (%)

183 (46)

221 (56)

Median (months)

25.0

19.9

HR (95% CI)

p-value

0.74 (0.61, 0.90)

0.004 (nominal)

Objective Response Rate

Number of evaluable patients5

161

160

Number of patients with responses (%)

58

48

Odds ratio (95% CI)

p-value

1.60 (1.02, 2.53)

0.0409 (nominal)

1. Investigator-assessed PFS data; Interim analysis with 50% maturity (394 events in 796 patients)
2. Assessed by blinded independent central review (BICR)
3. OS analysis was done at 29% maturity (228 events in 796 patients) and boundary for significance was 0.001 (2-sided); statistical significance not reached. Survival follow up continues and further analyses were planned.
4. Not reached
5. Patients with measurable disease at baseline as per RECIST 1.1 criteria, investigator assessment.

LYNPARZA is approved in the U.S. for patients with HRR gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone and in the European Union, Japan and China for patients with BRCA-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent (NHA).

About PROpel

PROpel (ClinicalTrials.gov, NCT03732820) is a randomized, double-blind, multi-center Phase 3 trial testing the efficacy, safety and tolerability of LYNPARZA versus placebo when given in addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the first-line setting. Men in both treatment groups also received either prednisone or prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints include OS, PFS2 and TFST.

The trial enrolled men independent of HRR gene mutation status. They may have previously been treated with docetaxel at a prior stage of disease. The trial excluded men with prior treatment with abiraterone. Treatment with any other NHA must have been stopped one year or longer prior to randomization. Men must have an Eastern Cooperative Oncology Group performance status of 0-1 and be a candidate for abiraterone treatment with documented evidence of progressive disease.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab

Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%) and headache (14%).

In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%) and decrease in platelets (35%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%) and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

INDICATIONS for LYNPARZA in the United States

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab

In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

a deleterious or suspected deleterious BRCA mutation and/or
genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced gBRCAm Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

gBRCAm, HER2-Negative Metastatic Breast Cancer

For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

About LYNPARZA (olaparib)

LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

About Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is the second most common cancer in men globally and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body, despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20% of patients with advanced prostate cancer will develop CRPC within five years, and at least 84% of these patients will have metastases at the time of CRPC diagnosis. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize certain oncology products including LYNPARZA, the world’s first PARP inhibitor, for multiple cancer types. Working together, the companies will develop these products in combination with other potential new medicines and as monotherapies. Independently, the companies will develop these oncology products in combination with their respective PD-L1 and PD-1 medicines.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On February 14, 2022 PharmaCyte Biotech, Inc. (NASDAQ: PMCB), a biotechnology company focused on developing cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported an update on PharmaCyte’s activities to lift the U.S. Food and Drug Administration’s (FDA) clinical hold on PharmaCyte’s treatment for locally advanced, inoperable pancreatic cancer (LAPC) (Press release, PharmaCyte Biotech, FEB 14, 2022, View Source [SID1234608086]). After submission of an initial Investigational New Drug Application (IND), the FDA requested additional studies and information as a prerequisite for approval of PharmaCyte’s IND. A number of additional studies and assays have already been completed; several others are quite lengthy and are underway or are slated to begin soon. As each study and assay is completed, the results are being compiled and will make up PharmaCyte’s complete IND submission package to the FDA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, explained, "Given our treatment is a biologic and our technology is a one of a kind live-cell encapsulation, we completely understand the FDA’s need for more information. We are confident that with the data we’re producing in our additional studies and assays that the FDA will grant us an open IND just as the FDA granted us the Orphan Drug Designation for our treatment for LAPC.

"Last June, we provided an update on efforts being made by our team of regulatory and scientific experts that are addressing the FDA’s requirements to have the clinical hold lifted. Today, we would like to update that list and explain where we are in the process of delivering our updated IND package to the FDA. We have brought additional regulatory and scientific experts onboard the team, and we continue to engage closely with leading Contract Research Organizations (CROs) and our partner Austrianova to ensure a successful IND submission.

"We also want to make it clear that PharmaCyte and its service providers are under the same constraints as everyone else globally with supply chain issues, Covid related delays, and late delivery of materials that are needed to complete studies and assays required by the FDA. This also applies to the manufacturing of empty capsules and encapsulated live cells that are necessary to complete many of these required studies and assays. Moreover, many of the laboratories that are conducting our studies and assays are being met with long delays in receiving the consumables needed to conduct the specific studies for which they are responsible. So, we’re at the mercy of what is a global problem, which obviously makes it more difficult to offer any accurate timelines for completion of the FDA required assays and studies."

Below is the list of items on which PharmaCyte has been working, including updates on those tests previously reported.

Additional Regulatory Expertise Added to IND Team – In addition to its established team of experts, PharmaCyte has retained Biologics Consulting as a fresh set of regulatory eyes to perform a regulatory "Gap Analysis" and to assist with PharmaCyte’s IND submission. Biologics Consulting is a full-service regulatory and product development consulting firm for biologics, pharmaceuticals and medical devices and has personnel with extensive FDA experience. Although it took a lengthy amount of time to onboard Biologics Consulting, this should augment PharmaCyte’s ability to submit an acceptable IND to the FDA.
Stability Studies on PharmaCyte’s Clinical Trial Product – PharmaCyte has now successfully completed a product stability study after 3, 6, 9, 12 and 18-months of storage frozen at -80C on PharmaCyte’s clinical trial product known as CypCaps, including container closure integrity testing for certain timepoints. The next time point in this ongoing stability study will be at 24 months of product stability of the CypCaps. This 24-month time point analysis is ready to commence, and data will be available in the coming weeks.
Additional Studies Requested by the FDA – PharmaCyte has designed and commenced various additional studies requested by the FDA, including a stability study on the cells from its Master Cell Bank (MCB) used to make the CypCaps. PharmaCyte is already at the 3-year stability timepoint for the cells from its MCB.
Determination of the Exact Sequence of the Cytochrome P450 2B1 Gene – PharmaCyte has completed the determination of the exact sequence of the cytochrome P450 2B1 gene inserted at the site previously identified on chromosome 9 using state-of-the-art nanopore sequencing, a cutting edge, unique and scalable technology that permits real-time analysis of long DNA fragments. The result of this analysis of the sequence data confirmed that the genes are intact.
Biocompatibility Studies – PharmaCyte has designed and commenced 8 biocompatibility studies, 6 of which have been completed successfully. The remaining 2 studies are underway. Those studies are the Acute Systemic Toxicity Study of Empty Cellulose Sulphate Capsules in Mice and the Skin Sensitization Study of Empty Cellulose Sulphate Capsules in Guinea Pigs. To enable these studies to be performed, Austrianova manufactured and delivered an additional 400 syringes of empty capsules. Some of the data being generated will also be used to demonstrate comparability with the CypCaps successfully used in two earlier clinical trials for pancreatic cancer.
Micro-Compression and Swelling Assays – This project is underway. The project is developing and optimizing two reproducible methods for testing and confirming the physical stability and integrity of the CypCaps produced under GMP. These studies required the acquisition of new equipment by Austrianova as well as validation and integration into Austrianova’s Quality Control laboratory.
Break Force and Glide Testing – PharmaCyte is in the process of developing a protocol to measure whether the syringe, attached to the catheter when used to expel the capsules, will still have a break and glide force that is within the specification that PharmaCyte has established. PharmaCyte will set this specification based on the syringe/plunger manufacturer’s measured break and glide forces, or alternatively, accepted ranges for glide forces routinely used in the clinic.
CypCaps Capsules Compatibility with the Syringe and Other Components of the Microcatheter Delivery System – PharmaCyte has commenced studies designed to show that CypCaps are not in any way adversely affected by the catheters used by interventional radiologists to deliver them into a patient. Compatibility data is being generated to demonstrate that the quality of the CypCaps is maintained after passage through the planned microcatheter systems.
CypCaps Capsules and Cell Viability after Exposure to Radiological Contrast Medium – PharmaCyte has designed and commenced a project to test the effect of the exposure of CypCaps to two routinely used types of contrast medium that interventional radiologists use to implant the CypCaps in a patient. The contrast medium is used to visualize the blood vessels during implantation of the CypCaps.
Master Drug File Information- Austrianova is providing additional detailed confidential information to the FDA on the manufacturing process, including information on the improvements and advancements made to the product since the last clinical trials were conducted with respect to reproducibility and safety. However, Austrianova has not changed the overall physical characteristics of the CypCaps. PharmaCyte is supporting Austrianova financially in this work.
Additional Documentation Requested by the FDA – PharmaCyte is in the process of updating its documentation including extending its discussion on immunological aspects of its LAPC treatment.
Pig Study – Finally, the Company has designed a study in pigs to address biocompatibility and long-term implantation and dispersion of the CypCaps. This animal study will complement the positive data already available from the previous human clinical trials showing the safety of CypCaps implantation in human patients.

On February 14, 2022 Datar Cancer Genetics Inc reported that the US Food and Drug Administration (FDA) has granted ‘Breakthrough Device Designation’ for its ‘TriNetra-Prostate’ blood test to detect early-stage prostate cancer (Press release, Datar Cancer Genetics, FEB 14, 2022, View Source [SID1234608106]). This is the second test from the Company that has received the Breakthrough Device Designation from the US FDA. Last year, the Company’s early-stage breast cancer detection test became the first such test to receive the Breakthrough Device Designation.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In the United States, prostate cancer is the third most common type of cancer; each year, more than 200,000 men are detected with prostate cancer and is associated with more than 32,000 deaths. The test can identify individuals who are more likely to harbour cancer in the prostate and aids clinical decision making such as the need to undergo a biopsy for confirmatory diagnosis.

Studies have shown that TriNetra-Prostate can detect early-stage cancer with high accuracy (>99%) without any false positives. TriNetra-Prostate requires 5 ml blood and is indicated for males of age 55-69 years with serum PSA of 3 ng/mL or higher. TriNetra-Prostate is based upon the detection of prostate adenocarcinoma specific Circulating Tumor Cells (CTCs) in the blood.

"The breakthrough device designation is a recognition of the potential benefits of TriNetra-Prostate in the clinical setting. The test can help reduce the number of biopsies among individuals with benign conditions of the prostate and it can also improve detection rates among those who do have prostate cancer. With our proprietary CTC-enrichment and detection technology, there is virtually no risk of false positives among individuals who do not have prostate cancer," said Dr Vineet Datta, Executive Director of the Company. The test has previously received CE certification and is already available in Europe as ‘Trublood-Prostate’.

The Breakthrough Device Designation is granted by the FDA for devices that demonstrate a potential for more effective diagnosis of life-threatening diseases such as cancer. The Breakthrough Devices Program intends to provide patients and healthcare providers with timely access to medical devices granted such designation by prioritized review to expedite development and assessment.