On May 26, 2022 Carisma Therapeutics Inc., a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported that two presentations including findings of its lead candidate, CT-0508, accepted for presentation at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, June 3-7 (Press release, Carisma Therapeutics, MAY 26, 2022, View Source [SID1234615141]). The company will present the latest data from its landmark CT-0508 chimeric antigen receptor macrophage (CAR-M) trial for patients with advanced metastatic HER2 overexpressing solid tumors, reaffirming safety and feasibility of its proprietary engineered cell therapy platform. Clinical trial design for phase 1 study of adenovirally transduced autologous macrophages, a second CT-0508 study, was also accepted for presentation.

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In the abstract "A Phase 1, first-in-human (FIH) study of the anti-HER2 CAR Macrophage CT-0508 in subjects with HER2 overexpressing solid tumors," Kim A. Reiss, MD, principal investigator of the Phase 1 clinical trial and an Assistant Professor of Hematology-Oncology at the Perelman School of Medicine at the University of Pennsylvania (Penn), will present an update on the ongoing clinical trial. The findings are the first clinical data of genetically engineered macrophages in humans and demonstrate that CT-0508 was well tolerated after infusion and there were no dose-limiting toxicities reported to date in the current study. CT-0508 was also successfully manufactured using macrophages obtained from heavily pre-treated, advanced solid tumor patients and showed high chimeric antigen receptor (CAR) expression, viability, and purity. The data provide the first clinical demonstration of the CAR-M mechanism of action, exhibiting tumor infiltration, remodeling of the solid tumor microenvironment, and early indications of T-cell activation.

"This additional patient data reinforces the potential of the CAR-M platform, which may have applicability across other therapeutic areas in addition to HER2 over expressing cancers," said Debora Barton, MD, Chief Medical Officer at Carisma Therapeutics. "We look forward to continuing the CT-0508 clinical trial to further observe how our CAR-M therapy can potentially address the unmet needs of patients with hard-to-treat cancers."

Also accepted for presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting is, "A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors," overview of the design of the Phase 1 clinical trial, also presented by Dr. Reiss.

Both of the abstracts will be presented at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting in the "Developmental Therapeutics—Immunotherapy" poster session on June 5.

Editor’s Note: Carisma has licensed certain Penn-owned intellectual property from the University of Pennsylvania, and Penn’s Perelman School of Medicine receives sponsored research and clinical trial funding from the company. Penn may also be entitled to receive additional financial benefits from technologies licensed and optioned to Carisma in the future. In addition, Penn is a co-founder of the company and holds equity interests in Carisma.

About CT-0508
CT-0508 is a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M). It is being evaluated in a landmark Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies or who do not respond to treatment. We are selecting participants who have tumors of any anatomical origin, but with the commonality of overexpressing the HER2 receptor on the cell surface, which is the target for our CAR-M. The Phase 1 clinical trial is first-of-its-kind, marking the first time that engineered macrophages are being studied in humans. The trial continues to enroll patients at five U.S. sites, including Penn; the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill; City of Hope in Duarte, California; University of Texas MD Anderson Cancer Center in Houston, Texas; and Sarah Cannon Research Institute at Tennessee Oncology – Nashville.

On May 26, 2022 Invitae (NYSE: NVTA), a leading medical genetics company, reported eight studies to be presented at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting held in Chicago from June 3-7, 2022 (Press release, Invitae, MAY 26, 2022, View Source [SID1234615158]). While the research covers a variety of cancer types, stages and patient demographics, all of the data underscore the importance of universal genetic testing to improve health outcomes for all cancer patients.

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Invitae’s (NVTA) mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. www.invitae.com (PRNewsFoto/Invitae Corporation)

Inherited genes impact risk for developing melanoma

Melanoma—the most frequent cause of skin cancer-related deaths—is often perceived as a cancer caused by environmental factors. While sun exposure plays a role in most melanoma tumors, a new, first-of-its-kind study by Cleveland Clinic and Invitae found that genetics also play a critical role in the likelihood of developing melanoma. In fact, the study found that 15% of individuals with melanoma have inherited variants in a variety of genes associated with cancer predisposition syndromes, demonstrating multiple potential etiologies. What’s more, genes previously associated with inherited melanoma comprised less than half of pathogenic variants (48%); and the majority of germline variants were in cancer predisposition genes that are not traditionally associated with melanoma. This study shows that all patients with melanoma should undergo genetic testing, whether or not they have a family history of cancer, or a personal history of sun exposure.

"Previously, it was thought that few melanoma patients would demonstrate a pathogenic germline variant in cancer susceptibility genes indicating an inherited component to their melanoma risk," said Joshua Arbesman, M.D., dermatologist at Cleveland Clinic and senior author of the study. "Our results, however, suggest that about 1 in 6 melanoma patients would have an inherited variant in cancer genes. This means that these particular patients would benefit from cancer specific screening (separate from skin screening) that could catch other cancers earlier. We found similar results using multiple datasets with variable inclusion criteria, suggesting this may be potentially applicable to many melanoma patients."

Research shows prostate cancer testing guidelines out of date

A separate study of prostate cancer patients confirmed similar findings that limiting genetic testing to those patients who meet NCCN guidelines deprives individuals and clinicians of actionable information. In data from the ongoing PROCLAIM study, conducted primarily in community urology clinics, 50% of pathogenic variants in patients with prostate cancer would be missed if genetic testing were done based on NCCN guidelines. The study also showed current guidelines are poorly suited to detect pathogenic variants in traditionally underrepresented populations, suggesting a transition to universal testing may be the most expeditious strategy to mitigate this potential healthcare disparity. Appropriately, patients with cancer-linked pathogenic variants in the study were more likely to have recommendations made by their clinicians regarding changes to treatment, follow up and cascade testing than those with negative or uncertain results. Clinicians made genetics-based recommendations across the spectrum of patients tested, including those not meeting NCCN criteria, and those with low-grade and non-metastatic disease.

"Guidelines from national and international oncologic societies are regularly updated but not always as quickly as our understanding of gene-disease relationships in the rapidly evolving field of genomic sequencing, and thus there are real world implications affecting patient-physician decision making as well as patient access to affordable and geographically accessible genetic testing," said Dr. Neal Shore, lead author of the study. "This study shows that germline genetic testing has a significant impact on prostate cancer patient care, and that urologists, oncologists, their patients and patients’ family members would benefit from making germline genetic testing a routine practice for all prostate cancer patients."

Genetic changes impact colorectal cancer care

In a third study of more than 34,000 colorectal cancer patients—the largest study of its kind to date—researchers found that 13% of patients had inherited pathogenic variants that could potentially impact patient eligibility for precision therapy, access to clinical trials and/or inform screening for future cancers. This study, in collaboration with investigators at the University of Pennsylvania Perelman School of Medicine, showed rates > 7.8% of clinically actionable pathogenic gene variants independent of age group, racial/ethnic group and panel size. The study saw a lower rate of pathogenic variants in known cancer genes in Hispanic patients and a higher rate of variants of uncertain significance (VUS) in Black, Asian and Hispanic patients. This underscores the historical underrepresentation of these patients in genetics studies, and the ongoing need to mitigate the associated healthcare disparities.

"In the United States, colorectal cancer is the third leading cause of cancer-related deaths in men and in women, and the second most common cause of cancer deaths when men and women are combined," said Ed Esplin, M.D., Ph.D., FACMG, FACP, clinical geneticist at Invitae. "The genetic variants we inherit play a crucial role in providing patients access to approved precision therapies and clinical trials for colorectal cancer treatment, and to quantify and mitigate the risk of colorectal cancer in their at-risk family members. This study shows the importance of broadening genetic testing criteria to include all patients with colorectal cancer, regardless of age, race/ethnicity or family history."

Additional clinical research from Invitae at ASCO (Free ASCO Whitepaper)

Invitae is presenting additional research at ASCO (Free ASCO Whitepaper) in collaboration with academic institutions and research partners that showcase the importance of genetic testing to guide cancer diagnosis and precision medicine treatment. This effort is consistent with the primary objectives of the Cancer Moonshot to reduce the death rate from cancer by 50 percent and improve the experience of people and their families living with cancer. All of the presentations highlight Invitae’s commitment to improving the adoption of germline genetic testing among physicians and people living with cancer, highlighting the impact of cancer genetics on cancer patients from underserved populations, and effectively illustrating its clinical utility in improving patient care.

2022 ASCO (Free ASCO Whitepaper) presentations:

Poster 60/Abstract 4569: Titled: Germline variants across self-reported racial populations with urothelial carcinoma (UC). Presenter: Amin Nassar, M.D. — Saturday, June 4, 2022 at 1:15 p.m. CDT.
Abstract 10500: Titled: Democratizing germline genetic testing and its impact on prostate cancer clinical decision-making. Presenter: Neal D. Shore, M.D. — Monday, June 6, 2022 at 8:00 a.m. CDT.
Abstract 10504: Titled: Clinical implications of germline genetic testing stratified by ethnicity in a large colorectal cancer cohort. Presenter: Sarah Coughlin, M.D. — Monday, June 6, 2022 at 8:00 a.m. CDT.
Poster 464/Abstract 10589: Titled: Integrated germline and somatic cancer testing provides opportunity to identify cancer risk and resolve variant origins. Presenter: King Das, M.D. — Monday, June 6, 2022 at 1:15 p.m. CDT.
Poster 455/Abstract 10580: Titled: Implementation of universal, pan-cancer germline genetic testing in cancer patients in Jordan. Presenter: Hikmat Abdel-Razeq, M.D. — Monday, June 6, 2022 at 1:15 p.m. CDT.
Poster 463/Abstract 10588: Titled: Universal genetic testing versus guideline-directed testing for hereditary cancer syndromes among traditionally underrepresented patients in a community oncology program. Presenter: Jeremy Clifton Jones, M.D. — Monday, June 6, 2022 at 1:15 p.m. CDT.
Poster 401/Abstract 10523: Titled: Germline predisposition in oncologic and dermatologic melanoma cohorts. Presenter: Pauline Funchain, M.D. — Monday, June 6, 2022 at 4:30 p.m. CDT.
Online Publication: Titled: Patterns and prevalence of pathogenic germline mutations using multi-gene panel testing in patients with ovarian cancer. The Jordanian Exploratory Cancer Genetics (Jo-ECAG) ovarian study. Lead Author Hikmat Abdel-Razeq, M.D.

On May 26, 2022 Aadi Bioscience, Inc. (NASDAQ: AADI), a biopharmaceutical company focused on developing and commercializing precision therapies for genetically defined cancers with alterations in mTOR pathway genes, reported presentation of a poster entitled, "nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program" at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held online and in person from June 3-7 in Chicago, IL (Press release, Aadi Bioscience, MAY 26, 2022, View Source [SID1234615176]).

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The data represent exploratory biomarker results reported from the final analysis of mTOR inhibitor-naïve advanced malignant PEComa patients treated with nab-sirolimus in Aadi’s Advanced Malignant PEComa Trial (AMPECT) trial as well as an analysis of prior mTOR inhibitor exposed advanced malignant PEComa patients treated with nab-sirolimus in the Expanded Access Program (EAP) through June 2021. While the AMPECT and EAP studies cannot be directly compared, the findings of each show a greater clinical benefit in the patients harboring TSC1 or TSC2 alterations who received nab-sirolimus compared to all evaluable patients, regardless of prior mTOR inhibitor exposure.

"Given that inactivating alterations in TSC1 or TSC2 are potentially targetable biomarkers for mTOR inhibition, the exploratory biomarker results from these studies are encouraging as they support the rationale for our ongoing PRECISION 1 Phase 2 registrational trial," said Neil Desai, Ph.D., Founder, President and Chief Executive Officer of Aadi. "The response rates to nab-sirolimus in both AMPECT and the EAP showed similar positive trends in patients with TSC1 or TSC2alterations, regardless of prior mTOR inhibitor exposure."

Nab-sirolimus is an albumin-bound mTOR inhibitor approved by the U.S. Food and Drug Administration (FDA) as FYARRO for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The data to be presented include 31 mTOR inhibitor naïve patients from the AMPECT trial and 16 patients with prior mTOR inhibitor treatment from the EAP, all of which were treated with nab-sirolimus. Of those patients with TSC1or TSC2 alterations in the AMPECT trial, 64% had a complete or partial response versus a 39% response rate for all evaluable patients in the trial. Of those patients with TSC1 or TSC2 alterations in the EAP, 44% had a partial response versus 25% for all evaluable patients in the program.

Presentation details:

Presentation details:

Abstract Title: "nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program" (Dickson, et al.)
Abstract Number: 11574
Session Title: Sarcoma
Session Date: Sunday, June 5, 2022
Session Time: 6 am ET/9am PT
Presenter: Mark Andrew Dickson, MD
About the AMPECT Trial

The AMPECT trial (NCT02494570) evaluated the efficacy and safety of nab-sirolimus and was the first prospective registrational study in advanced malignant PEComa. AMPECT was a Phase 2, open-label, single-arm, multi-center study in patients with advanced malignant PEComa to determine the efficacy and safety of nab-sirolimus (data cutoff as of June 2021). Data from this trial were the basis of the FDA approval of FYARRO in advanced malignant PEComa.

In the trial, the overall response rate as assessed by independent review was 39% (12/31), with 2 patients converting from a Partial Response to a Complete Response after prolonged follow up. The median duration of response has not been reached with a median follow-up of 36 months, and a range of 5.6 to 55.5+ months and ongoing. Among responders, 92% had a response lasting greater than or equal to 6 months; 67% had a response lasting greater than or equal to 12 months; and 58% had a response lasting greater than or equal to 2 years. As is the case with other therapeutics of the mTOR class, the FYARRO prescribing information includes warnings and precautions related to stomatitis, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease/non-infectious pneumonitis, hemorrhage, and hypersensitivity reactions. Grade 3 non-hematologic events occurring in ≥ 10% of patients included stomatitis, rash, fatigue and infections. Grade 3 laboratory abnormalities occurring in ≥ 10% of patients that worsened from baseline included lymphocytopenia, increased glucose, and decreased potassium.

About the Aadi Expanded Access Program (EAP) for nab-sirolimus

Between closure of the AMPECT trial and nab-sirolimus commercial availability, an expanded access program (EAP; NCT03817515) allowed for the treatment of advanced malignant PEComa patients as well as other malignancies with relevant genetic mutations or mTOR pathway activation.

Amongst the patients on the EAP, sixteen with advanced malignant PEComa and prior mTOR inhibitor exposure were treated from July 2019 to July 2021. Prior mTOR inhibitor treatments included sirolimus, everolimus, temsirolimus and sapanisertib. Twelve patients had exposure to one prior mTOR inhibitor and four patients had exposure to >2 prior mTOR inhibitors. Fifty percent had progressive disease as best response on previous mTOR inhibitor treatment. Adverse events reported by treating physicians in the EAP were consistent with what was reported in AMPECT.

For detailed important safety information, please see below.

About FYARRO

FYARRO is an mTOR inhibitor indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

Important Safety Information

Contraindication

FYARRO is contraindicated in patients with a history of severe hypersensitivity to sirolimus, other rapamycin derivatives, or albumin.

Warnings and Precautions

Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, occurred in 79% of patients treated with FYARRO, including 18% Grade 3. Stomatitis was most often first reported within 8 weeks of treatment. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Myelosuppression

FYARRO can cause myelosuppression including anemia, thrombocytopenia and neutropenia. Anemia occurred in 68% of patients; 6% were Grade 3. Thrombocytopenia and neutropenia occurred in 35% of patients each. Obtain blood counts at baseline and every 2 months for the first year of treatment and every 3 months thereafter, or more frequently if clinically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Infections

FYARRO can cause infections. Infections such as urinary tract infections (UTI), upper respiratory tract infections and sinusitis occurred in 59% of patients. Grade 3 infections occurred in 12% of patients, including a single case each of a UTI, pneumonia, skin, and abdominal infections. Monitor patients for infections, including opportunistic infections. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Hypokalemia

FYARRO can cause hypokalemia. Hypokalemia occurred in 44% of patients including 12% Grade 3 events. Monitor potassium levels prior to starting FYARRO and implement potassium supplementation as medically indicated. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Hyperglycemia

FYARRO can cause hyperglycemia. Hyperglycemia occurred in 12% of patients treated with FYARRO, all of which were Grade 3 events. Monitor fasting serum glucose prior to starting FYARRO. During treatment, monitor serum glucose every 3 months in non-diabetic patients, or as clinically indicated. Monitor serum glucose more frequently in diabetic patients. Based on the severity of the adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Interstitial Lung Disease / Non-Infectious Pneumonitis

FYARRO can cause interstitial lung disease (ILD) / non-infectious pneumonitis. ILD / non-infectious pneumonitis occurred in 18% of patients treated with FYARRO, of which all were Grades 1 and 2. Based on the severity of the adverse reaction, withhold, reduce the dose, or permanently discontinue FYARRO.

Hemorrhage

FYARRO can cause serious and sometimes fatal hemorrhage. Hemorrhage occurred in 24% of patients treated with FYARRO, including Grade 3 and Grade 5 events in 2.9% of patients each. Monitor patients for signs and symptoms of hemorrhage. Based on the severity of adverse reaction, withhold, resume at reduced dose, or permanently discontinue FYARRO.

Hypersensitivity Reactions

FYARRO can cause hypersensitivity reactions. Hypersensitivity reactions, including anaphylaxis, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been observed with administration of the oral formulation of sirolimus. Hypersensitivity reactions including anaphylaxis have been observed with human albumin administration. Monitor patients closely for signs and symptoms of infusion reactions during and following each FYARRO infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Monitor patients for at least 2 hours after the first infusion and as clinically needed for each subsequent infusion. Reduce the rate, interrupt infusion, or permanently discontinue FYARRO based on severity and institute appropriate medical management as needed.

Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action, FYARRO can cause fetal harm when administered to a pregnant woman. In animal studies, mTOR inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use effective contraception while using FYARRO and for 12 weeks after the last dose.

Male Infertility

Azoospermia or oligospermia may be observed in patients treated with FYARRO. FYARRO is an anti-proliferative drug and affects rapidly dividing cells such as germ cells.

Immunizations and Risks Associated with Live Vaccines

No studies in conjunction with immunization have been conducted with FYARRO. Immunization during FYARRO treatment may be ineffective. Update immunizations according to immunization guidelines prior to initiating FYARRO, if possible. Immunization with live vaccines is not recommended during treatment and avoid close contact with those who have received live vaccines while on FYARRO. The interval between live vaccinations and initiation of FYARRO should be in accordance with current vaccination guidelines for patients on immunosuppressive therapies.

Risk of Transmission of Infectious Agents with Human Albumin

FYARRO contains human albumin, a derivative of human blood. Human albumin carries only a remote risk of transmission of viral diseases because of effective donor screening and product manufacturing processes. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been associated with albumin.

Adverse Reactions

Adverse Reactions in PEComa

The most common adverse reactions (≥30%) were stomatitis in 27 (79%) patients; fatigue and rash in 23 (68%) patients each; infection in 20 (59%) patients; nausea and edema in 17 (50%) patients each; diarrhea, musculoskeletal pain and decreased weight in 16 (47%) patients each; decreased appetite in 15 (44%) patients; cough in 12 (35%) patients; and vomiting and dysgeusia in 11 (32%) patients each.

Laboratory Abnormalities in PEComa

The most common Grade 3 to 4 laboratory abnormalities (≥6%) were decreased lymphocytes in 7 (21%) patients; increased glucose and decreased potassium in 4 (12%) patients each; decreased phosphate in 3 (9%) patients; and decreased hemoglobin and increased lipase in 2 (6%) patients each.

Dosage interruptions

Dose interruptions of FYARRO due to an adverse reaction occurred in 22 (65%) patients. Adverse reactions which required dosage interruption in >5% of patients included stomatitis in 6 (18%) patients, pneumonitis in 5 (15%) patients, anemia in 3 (9%) patients, and dehydration, dermatitis acneiform, and thrombocytopenia in 2 (6%) patients each.

Dose reduction

Dose reductions of FYARRO due to an adverse reaction occurred in 12 (35%) patients. Adverse reactions which required dose reductions in > 5% of patients included stomatitis and pneumonitis in 3 (9%) patients each.

Drug Interactions

Reduce the dosage of FYARRO to 56 mg/m2 when used concomitantly with a moderate or weak cytochrome P-450 3A4 (CYP3A4) inhibitor. Avoid concomitant use with drugs that are strong CYP3A4 and/or P-glycoprotein (P-gp) inhibitors and inducers and with grapefruit and grapefruit juice.

Use in Specific Populations

Pregnancy

Based on the mechanism of action and findings in animals, FYARRO can cause fetal harm when administered to a pregnant woman. Advise females of the potential risk to a fetus and to avoid becoming pregnant while receiving FYARRO.

Lactation

Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action. Because of the potential for serious adverse reactions in breastfed infants from FYARRO, advise women not to breastfeed during treatment with FYARRO and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

FYARRO can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to starting treatment with FYARRO. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with and for at least twelve weeks after the last dose of FYARRO. Advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with FYARRO and for at least twelve weeks after the last dose of FYARRO. Although there are no data on the impact of FYARRO on fertility, based on available clinical findings with oral formulation of sirolimus and findings in animals, male and female fertility may be compromised by the treatment with FYARRO.

Pediatric

The safety and effectiveness of FYARRO in pediatric patients have not been established.

Geriatric Use

Of the 34 patients treated with FYARRO, 44% were 65 years of age and older, and 6% were 75 years of age and older. Clinical studies of FYARRO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Hepatic Impairment

FYARRO is not recommended for use in patients with severe hepatic impairment. Reduce FYARRO dosage in patients with mild or moderate hepatic impairment.

Full prescribing information can be found here.

About the PRECISION 1 Trial

The PRECISION 1 trial is a multi-center, open-label, tumor-agnostic pivotal study, of nab-sirolimus designed as a basket trial that will evaluate approximately 120 adult and adolescent patients with solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes. The trial will have two independent arms of 60 patients each to separately evaluate patients with either TSC1or TSC2 inactivating alterations. Aadi has received Fast Track designation to evaluate nab-sirolimus in this indication from the FDA. The first patient in the PRECISION 1 trial was dosed in March 2022.

On May 26, 2022 Harpoon Therapeutics, Inc. (Nasdaq: HARP), a clinical-stage immunotherapy company developing novel T cell engagers, reported interim safety and efficacy data from the ongoing dose escalation and expansion study evaluating HPN328, Harpoon’s half-life extended TriTAC targeting delta-like canonical Notch ligand 3 (DLL3), for the treatment of SCLC and other neuroendocrine cancers (Press release, Harpoon Therapeutics, MAY 26, 2022, View Source [SID1234615193]). The first scientific presentation of these interim data will be featured in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2022, taking place in Chicago from June 3-7.

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The encouraging interim results, as of the data cut-off date of April 21, 2022, showed that HPN328 demonstrated anti-tumor activity and a favorable safety profile in patients with SCLC, neuroendocrine prostate cancer and other neuroendocrine cancers. Seven of 18 patients (39%) had a decrease in sum of target lesion diameters, with 3 of 11 patients (27%) with SCLC across all dose cohorts experiencing a greater than 30% decrease in sum of target lesion diameters. Additionally, 4 of 6 patients (67%) with SCLC treated at greater than or equal to 1.215mg/week experienced a decrease in sum of target lesion diameters. To date, there have been no dose-limiting toxicities observed and no discontinuations due to adverse events. Grade 1-2 CRS occurred in 22% of patients. No grade 3 or higher CRS or any immune effector cell associated neurotoxicity syndrome (ICANS) events have been observed.

"DLL3 is expressed on the surface of tumor cells in more than 70% of small cell carcinomas, including small cell lung cancer, neuroendocrine prostate cancer, and other small cell neuroendocrine cancers, and HPN328 is specifically engineered to hit this target," said Himisha Beltran, M.D., of Dana-Farber Cancer Institute, Boston, a Principal Investigator in this study. "The encouraging single-agent clinical activity observed to date in patients that have received multiple prior lines of therapy, combined with the favorable safety profile, suggest the investigational T cell engager HPN328 may offer meaningful clinical benefits as a monotherapy for patients expressing DLL3. I look forward to the clinical results from further investigations with this promising drug candidate."

To date, study investigators have observed 1 confirmed partial response with a 53% decrease in sum of target lesion diameters at week 10 in a patient with SCLC who previously achieved a best overall response of stable disease on platinum-based chemo-immunotherapy. Another SCLC patient treated with 3 prior lines of therapy achieved a 65% decrease in sum of target lesion diameters with deepening of target lesion response, with treatment ongoing beyond six months. There were 6 instances of patients with best overall response of stable disease (4 SCLC, 1 neuroendocrine prostate cancer, and 1 thymic atypical carcinoid).

"We are pleased to share our continued progress with the HPN328 anti-DLL3 T cell engager clinical program and these interim data in a peer-reviewed setting, providing further clinical validation for our TriTAC technology in solid tumors," said Julie Eastland, President and CEO of Harpoon Therapeutics. "Given the clinical activity and acceptable tolerability profile observed to date, we look forward to continuing dose escalation, with the goal of identifying a dose for expansion studies by the end of the year, as we further explore the full potential of HPN328 as both a single agent and in future combination studies with atezolizumab to help patients with cancer."

Details of the ASCO (Free ASCO Whitepaper) poster presentation are as follows:

Title: Interim results of an ongoing phase 1/2a study of HPN328, a tri-specific, half-life extended, DLL3-targeting, T cell engager, in patients with small cell lung cancer and other neuroendocrine cancers
Abstract/Poster: 8566/193
Session Title: Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers
Session Date and Time: Monday, June 6, 8:00 a.m. to 11:00 a.m. CT

About HPN328

HPN328, a Tri-specific T cell Activating Construct (TriTAC), is being evaluated as monotherapy in an ongoing open-label, multicenter two-part study to assess the safety, tolerability and pharmacokinetics in patients with advanced cancers associated with expression of DLL3. Part 1 of the study is designed to determine dosage(s) for further evaluation in expansion cohorts during Part 2.

In March 2022, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to HPN328 for the treatment of SCLC.

For additional information on the HPN328 clinical study, please go to ClinicalTrials.gov and use Identifier NCT04471727.

On May 26, 2022 FibroGen, Inc. (NASDAQ: FGEN) reported that Enrique Conterno, Chief Executive Officer, will participate in a fireside chat at the Jefferies Healthcare Conference on Thursday, June 9 at 1:30pm EDT (Press release, FibroGen, MAY 26, 2022, View Source [SID1234615061]).

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A live audio webcast of the event will be available on the "Events & Presentations" section of the FibroGen Investors webpage at www.fibrogen.com. A replay will be available for approximately 30 days.