Uncategorized – Page 9535 – 1stOncology™: Cancer Intelligence Service

Gracell Biotechnologies Reports Long-term Follow-up Data on TruUCAR-enabled GC027 in Relapsed/Refractory T-ALL at the AACR 2021 Annual Meeting

On April 10, 2021 Gracell Biotechnologies Inc. (NASDAQ: GRCL) ("Gracell"), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, reported long-term follow-up data on their TruUCAR-enabled allogeneic product candidate GC027 for the treatment of adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) in an e-poster presentation at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 10 (Press release, Gracell Biotechnologies, APR 10, 2021, View Source [SID1234577873]).

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TruUCAR-enabled GC027 is a first-in-human, off-the-shelf allogeneic CAR-T stand-alone therapy targeting CD7. An ongoing, multi-center investigator-initiated Phase 1 trial in China is evaluating the safety and efficacy of GC027 for the treatment of adults with r/r T-ALL. We first reported results as oral presentation at the AACR (Free AACR Whitepaper) 2020 Annual Meeting.

The updated data with a February 4, 2021 data cut-off represents long-term follow-up as well as additional patients treated. Patients had received a median of six prior lines of therapy and received a single infusion of TruUCAR GC027 in one of three dose levels: 0.6x107cells/kg, 1.0x107cells/kg or 1.5x107cells/kg. Six patients (100%) treated achieved a complete remission with or without complete blood count recovery (CR/CRi) and five of the six patients (83%) achieved minimum residual disease negative complete remission (MRD- CR). At 6 months post treatment, three out of five patients (60%) had maintained MRD- CR. After 18.5 months of follow up for the initial patients treated, one patient continued to be MRD- CR at 16.8 months. One patient maintained MRD- CR until 9 months and one patient with primary refractory disease (no response to VDP) maintained his MRD- CR status until month 7. One additional patient treated presented initially with a high tumor burden and extensive extramedullary (EM) disease. After treatment with GC027 and as confirmed by PET CT scan, all EM lesions resolved. The patient achieved MRD- CR at day 28.

All six patients tolerated a single infusion of TruUCAR GC027. No neurotoxicity events (ICANS) or acute graft-versus-host disease (aGvHD) were observed. Cytokine release syndrome (CRS) occurred in all patients and was managed with standard of care including Tocilizumab. Overall safety findings were consistent with previous observations.

"These data show promising long-term follow-up results in r/r T-ALL patients who have very limited treatment options available," commented Dr. Martina Sersch, M.D., Chief Medical Officer of Gracell. "With these findings, GC027 may have the potential to be developed as a single-infusion stand-alone allogeneic CAR-T therapy. We are looking forward to expediting the clinical development of our TruUCAR-enabled GC027 globally, as well as expanding into additional indications beyond T-ALL."

Presentation link: View Source
Abstract link: View Source!/9325/presentation/4633

About GC027
TruUCAR-enabled GC027 is a first-in-human, off-the-shelf allogeneic CAR-T therapy targeting CD7, currently being developed for the treatment of T-ALL in adults. GC027 is manufactured from T cells of human leukocyte antigen (HLA) unmatched healthy donors. Developed on our proprietary TruUCAR platform, GC027 utilizes dual-function CAR to specifically target a patient’s own T cells and natural killer (NK) cells that would otherwise be directed against the foreign, or allogeneic, CAR-T cells resulting in rejection by the patients. This novel design allows this allogeneic cell therapy to survive a patient’s immune system without the need for combination treatment with additional potent immunosuppressant and represents a differentiated monotherapy approach.

About T-ALL
T cell malignancies are a group of cancers involving T lymphocytes, including acute T cell lymphoblastic leukemia or T-ALL. Standard of care treatment for T-ALL includes chemotherapy, radiation therapy and stem cell transplantation. Standard chemotherapy regimens only result in 30% – 40% response rate with 6 months median Overall Survival among responders. Patients with T cell malignancies usually have high relapse and mortality rates. Relapsed patients have dismal prognosis with very limited treatment options and <10% of patients surviving beyond 5 years. Due to shared common surface antigens and potential contamination by malignant cells, development of CAR-T cell therapies for T-ALL is lagged behind. In addition, no new therapies have been approved for the treatment of T-ALL since the approval of Nelarabine (marketed by GlaxoSmithKline) by the FDA in 2005. Globally, approximately 64,000 patients are diagnosed with ALL every year with over approximately 6,000 expected to be diagnosed in the United States in 2020. T-ALL accounts for approximately 25% of ALL diagnoses in adults. 1

About TruUCAR
TruUCAR is Gracell’s proprietary technology platform and is designed to generate high-quality allogeneic CAR-T cell therapies that can be administered "off-the-shelf" at lower cost and with greater convenience. With differentiated design enabled by gene editing, TruUCAR is designed to control host vs graft rejection (HvG) as well as graft vs host disease (GvHD) without the need of being co-administered with immunosuppressive drugs.

The lead program of TruUCAR platform, GC027, is manufactured using T cells from non-HLA matched healthy donors. The TruUCAR platform utilizes novel designs of a dual-function CAR or dual-CAR to reduce HvG, eliminating the need of combination therapy with additional potent immunosuppressant to induce deeper immune suppression and enabling stand-alone allogeneic CAR-T cell therapy.

F-star Therapeutics Shows Differentiation of FS222 in 2021 AACR Poster

On April 10, 2021 F-star Therapeutics, Inc. (NASDAQ: FSTX), a clinical-stage biopharmaceutical company dedicated to developing next generation bispecific immunotherapies to transform the lives of patients with cancer, reported that preclinical data from FS222, a potentially best-in-class tetravalent bispecific antibody targeting both CD137 and PD-L1 will be presented in a poster at the 2021 American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place virtually from April 10-15 and May 17-21 (Press release, F-star, APR 10, 2021, View Source [SID1234578009]). Poster #1864, entitled ‘FS222, a Tetravalent Bispecific Antibody Targeting CD137 and PD-L1, is Designed for Optimal CD137 Interactions Resulting in Potent T cell Activation Without Toxicity’ will be available via on-demand viewing starting today, April 10, at 8:30 a.m. ET.

FS222 targets PD-L1, the immune checkpoint protein that regulates the balance of activated T cells in the immune system and is overexpressed on many solid tumors and CD137, a co-stimulatory molecule from the tumor necrosis factor receptor superfamily (TNFRSF), which is widely known to be upregulated on tumor-reactive CD8+ T cells or "killer T cells". Currently, only a minority of patients have a long-lasting response to monotherapies that block the PD-(L)1 pathway.

Neil Brewis, Chief Scientific Officer at F-star Therapeutics, said: "We are encouraged by the results of these latest preclinical studies of FS222, our tetravalent bispecific antibody targeting PD-L1 and CD137. This work further demonstrates that FS222’s tetravalent binding mechanism is the most efficient and effective format for bispecific antibodies. The early onset of activity and T cell proliferation gives us confidence that FS222 will allow for a wide range of treatment options."

FS222 was designed to be a potent human CD137/PD-L1 tetravalent conditional agonist with a unique combination of high affinity PD-L1 binding, and moderate affinity, but with high avidity, binding to CD137 on activated T cells to result in optimal receptor clustering. Previously, FS222 has been shown to exhibit a favorable safety profile in preclinical safety studies.

Tetravalent binding by FS222 demonstrated optimal activity in multiple preclinical pharmacology studies, outperforming classic heterodimeric bispecific antibodies. These data showed that there was no evidence of a hook effect, or bell-shaped dose response curve, in vitro, and coupled with FS222’s favorable safety profile, presents a potentially broad and differentiated therapeutic window. A murine surrogate mAb2 for FS222 had peripheral immunopharmacology, as shown by CD8+ T cell proliferation, at high dose levels, mirroring the in vitro data, whereby the tetravalent FS222 surrogate mAb2 outperforms other lower valency formats.

In January 2021, F-star announced that the first patient had been dosed in a Phase 1 clinical trial of FS222, a multicenter, open-label, first-in-human trial to evaluate the safety, tolerability, and early signs of efficacy of FS222 in adult patients diagnosed with advanced malignancies. The adaptive study design will allow for the early exploration of clinical activity of FS222 in a range of selected solid tumors that will guide future targeted clinical development.

Clovis Oncology Highlights Rubraca® (rucaparib) Clinical Data at AACR Virtual Annual Meeting 2021

On April 10, 2021 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that Phase 1 clinical data from studies exploring Rubraca in combination with Xtandi for the treatment of advanced prostate cancer (RAMP) and Rubraca monotherapy in advanced solid tumors in Japanese patients (RUCA-J) will be presented during week one of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (AACR) (Free AACR Whitepaper), taking place April 10-15, 2021 (Press release, Clovis Oncology, APR 10, 2021, View Source [SID1234577825]).

"We remain committed to understanding how Rubraca may benefit patients with cancer, and the data presented at AACR (Free AACR Whitepaper) further enhance our understanding in different patient populations and solid tumor types," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "The Phase 1b RAMP data for the combination of Rubraca and Xtandi in unselected mCRPC patients help inform the Alliance for Clinical Oncology-sponsored CASPAR Phase 3 trial which is expected to begin enrolling patients soon, and we look forward to learning more about the combination."

Following are details of the Clovis-sponsored presentations at AACR (Free AACR Whitepaper) 2021:

Poster Presentation 445: Genomic Characteristics and Response to Rucaparib and Enzalutamide in the Phase 1b RAMP Study of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients

Lead author: Arpit Rao, MBBS, University of Minnesota, Minneapolis, USA
Session: Clinical Research
Date/Time: April 10, 2021, 8:30 a.m. – 11:59 p.m. ET
Key Takeaways: The results of this study demonstrated that unselected patients with mCRPC who had progressed on androgen receptor (AR)-directed therapies reported declines in prostate-specific antigen (PSA) following treatment with a combination of rucaparib 600 mg twice daily and enzalutamide 160 mg once daily, and these declines were observed even in the presence of AR alterations and the absence of DNA damage repair gene alterations. The safety profile was consistent with that associated with each drug as a monotherapy, with no clinically significant drug-drug interactions observed with the combination. These data support further study of the combination in this patient population and the Phase 3 CASPAR study (Alliance A031902; NCT04455750) is expected to begin enrolling biomarker-unselected patients with mCRPC shortly.
Poster Presentation CT124: Evaluation of Rucaparib in Japanese Patients with a Previously Treated Advanced Solid Tumor

Lead author: Kenji Tamura, MD, PhD, National Cancer Center Hospital, Tokyo, Japan
Session: Phase I Clinical Trials
Date/Time: April 10, 2021, 8:30 a.m. – 11:59 p.m. ET
Key Takeaways: This study suggests rucaparib 600 mg taken twice daily had a manageable safety profile for Japanese patients with advanced solid tumors, including ovarian, prostate, endometrial, and pancreatic cancer. The pharmacokinetic profile of rucaparib in Japanese patients overlapped with that of Western patients. Among patients with measurable disease, 18.5% (5/27) achieved an objective response rate and 51.9% (14/27) had stable disease per RECIST v1.1. These results support further exploration of rucaparib 600 mg twice daily in Japanese patients.
The presentations can also be viewed at View Source .

About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca U.S. FDA Approved Indications

Ovarian Cancer

Rubraca is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated for the treatment of adult women with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca.

Prostate Cancer

Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Patients should be identified for treatment with Rubraca based on the presence of a deleterious BRCA mutation (germline and/or somatic) and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents. In TRITON2, MDS/AML was not observed in patients with mCRPC (n=209) regardless of homologous recombination deficiency (HRD) mutation.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. For males on Rubraca treatment who have female partners of reproductive potential or who are pregnant, effective contraception should be used during treatment and for 3 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common adverse reactions in TRITON2 (≥ 20%; Grade 1-4) were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.

Tachyon Presents Promising Preclinical Data on Its First-in-class Pan-KDM4 Epigenetic Regulator, TACH101

On April 10, 2021 Tachyon Therapeutics, Inc. ("Tachyon" or "the Company"), a research and development biotechnology company, reported a presentation of data of the Company’s novel compound, TACH101, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting (Press release, Tachyon Therapeutics, APR 10, 2021, View Source [SID1234577858]). TACH101, Tachyon’s lead product candidate, is a first-in-class, highly-selective inhibitor of KDM4 histone demethylase . AACR (Free AACR Whitepaper) is being held virtually from April 10-15 and May 17-21, 2021.

"We are excited to be presenting for the first time data on TACH101, a novel first-in-class inhibitor of KDM4," stated Frank Perabo, MD, PhD, CEO of Tachyon Therapeutics. "KDM4 is an important epigenetic regulator of processes responsible for genomic instability, replicative immortality, evasion of apoptosis, deficiency in DNA repair and ability to metastasize across multiple tumor types. Extensive preclinical work shows compelling data for TACH101 to have broad potential in cancer treatment. To date, no small molecule inhibitor of KDM4 has reached clinical stage development, thus Tachyon would be the first to investigate this mechanistic pathway in a clinical trial."

Highlights from the AACR (Free AACR Whitepaper) presentation are summarized below:

TACH101 was broadly effective in the majority of 300 cancer cell lines screened.
TACH101 treatment induced cell cycle arrest in a dose-dependent manner, increasing the proportion of cells in S-phase by up to 3.2-fold after 72 hours of treatment.
TACH101 was potent in inducing apoptosis in human colorectal, esophageal, and triple negative breast cancer cell lines; the half maximal effective concentrations (EC50s) were in the nanomolar levels (ranging from 33 – 92 nM).
In vivo, TACH101 demonstrated effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%.
TACH101-treated tumors showed a significant reduction in the population of cancer stem cells by 4.4-fold.
Pharmacokinetic studies showed TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog, and had little or no inhibitory effects on CYP enzyme activities.
"Changes in epigenetic regulation are present in all human cancers and act as the control center for a variety of cancer pathways," states Mike Clarke, MD PhD, one of the Founders of Tachyon Therapeutics. "TACH101 is able to halt cancer progression by blocking KDM4 which participates in a majority of these pathways. Being able to reverse these alterations at the core level has far-reaching implications for cancer prevention and treatment and we are looking forward to further explore the full potential of this drug candidate."

The poster presentation titled, "TACH101, a First-in-Class Pan-Inhibitor of KDM4 Histone Lysine Demethylases," is available for viewing on the AACR (Free AACR Whitepaper) Annual Meeting website at View Source!/9325/presentation/3226.

Sumitomo Dainippon Pharma Oncology Presents New Data from Investigational Pipeline of Novel Cancer Therapeutics at AACR Virtual Annual Meeting I 2021

On April 10, 2021 Sumitomo Dainippon Pharma Oncology, Inc., a clinical-stage company focused on research and development for novel cancer therapeutics, reported new findings on a range of investigational agents from the company’s pipeline at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Sumitomo Dainippon Pharma, APR 10, 2021, View Source [SID1234577874]).

The data presented at the meeting include preclinical and Phase 1 clinical data evaluating the potential anti-cancer activity of the PKM2 activator TP-1454, PIM inhibitor TP-3654, TNK1 inhibitor TP-5809 and CDK9 inhibitor alvocidib. Additionally, Sumitomo Dainippon Pharma Co., Ltd., the parent company of Sumitomo Dainippon Pharma Oncology (SDP Oncology), presented findings from preclinical studies of DSP-0509, a TLR7 agonist.

"As we advance our investigational agents, we are pleased to present the latest research on our diverse pipeline to the scientific community at the AACR (Free AACR Whitepaper) Virtual Annual Meeting," said Patricia S. Andrews, CEO and Global Head of Oncology, SDP Oncology. "These data reflect our relentless commitment to propelling drug discovery in oncology and our progress in advancing research in hematologic and solid malignancies."

Below are the details for the presentations:

Abstract Title

Details

Presenter

PKM2 Activation Modulates the Tumor-Immune Microenvironment and Enhances Response to Checkpoint Inhibitors in Preclinical Solid Tumor Models

Abstract #606