On June 4, 2021 Cyteir Therapeutics, a leader in the discovery and development of next-generation synthetically lethal therapies for cancer, reported the presentation of an interim analysis of the Phase 1 portion of a first-in-human Phase 1/2 study of CYT-0851 (Press release, Cyteir Therapeutics, JUN 4, 2021, View Source [SID1234583544]). CYT-0851 is an oral, small molecule inhibitor of RAD51-mediated homologous recombination. The presentation was given at an oral session of the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting.

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The Phase 1 portion of the trial began enrolling patients with advanced hematologic cancers and solid tumors in September 2019. Patients were treated with continuous 28-day cycles of increasing oral doses of CYT-0851. The primary objective of the ongoing Phase 1 study is to identify the maximum tolerated dose (MTD). The key secondary objectives are evaluation of the safety, pharmacokinetics, and preliminary anti-tumor activity.

As of the April 6, 2021 data cutoff, 35 patients were treated with CYT-0851 across eight dose-escalation cohorts. Thirty-five patients were evaluable for safety and 21 patients were evaluable for efficacy. Patients had a median of four prior lines of therapy. Twenty-three patients discontinued treatment due to progressive disease (19), patient decision (2), physician decision (1) or adverse event (1). The adverse event that led to discontinuation was an increase in the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) that was secondary to the patient’s cancer.

To date, CYT-0851 has been well-tolerated with 63% of patients reporting no treatment related adverse events. Thirteen patients (37.1%) experienced treatment-related adverse events with most events being low-grade. There have been no reported treatment-related Grade 4 or 5 events. The most common treatment-related adverse events were an increase in blood alkaline phosphatase levels (8.6%), fatigue (8.6%) and nausea (8.6%). There have been no reported dose-limiting toxicities, clinically significant myelosuppression, treatment discontinuations due to treatment-related adverse events, or treatment-related serious adverse events.

At the time of the data cutoff, there were 21 patients who were response evaluable. Three partial responses were observed in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and soft tissue sarcoma. The patients with DLBCL and FL had confirmed responses according to Lugano criteria and the patient with sarcoma had a response that was unconfirmed according to RECIST. Ten patients had a best response of stable disease and four patients have been on therapy for more than six months, including the three patients that responded to treatment.

The study continues to dose-escalate to identify the MTD and enrollment is ongoing in the 400mg once daily dose cohort. Upon identification of the MTD, a Phase 2 dose will be selected, and the Phase 2 expansion cohorts are expected to begin enrollment in the second half of 2021.

On June 4, 2021 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento") reported that the Company has entered into an additional collaborative agreement with NextGenNK Competence Center-associated research groups at the Department of Medicine, Huddinge, Karolinska Institutet ("KI") in Stockholm, Sweden, aimed at producing novel cell-based therapeutics using natural killer ("NK") cells derived from induced pluripotent stem cells ("iPSCs") (Press release, Sorrento Therapeutics, JUN 4, 2021, View Source [SID1234583543]). Sorrento and KI are collaborative partners in the Competence Center for the development of next-generation NK cell-based cancer immunotherapies ("NextGenNK") coordinated by KI.

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Under the agreement, Sorrento will provide know-how in the core chimeric antigen receptor ("CAR") and dimeric antigen receptor ("DAR") technologies and support the collaborative effort to develop new CAR-NK and DAR-NK candidates, as well as fund the translational validation of the technologies. Multiple product candidates will be developed and tested in the initial phase of the planned work, with the goal that the candidate products will qualify for further human clinical trials.

The foundational Sorrento research assets critical to this program are novel proprietary CAR and DAR constructs identified through Sorrento’s proprietary G-MAB fully human antibody library and previously validated as determinants of cell-based therapy potency against hematologic and solid tumors.

"It is a privilege to continue and extend our collaborative work with the distinguished KI faculty. We are proud to contribute our technologies to produce new optimized off-the-shelf adoptive NK cell immunotherapies," said Dr. Henry Ji, Chairman and CEO of Sorrento. "Our partnership with KI combines our know-how with the expertise of a world-renowned institution in the field of NK cell therapy. These types of partnerships are essential in advancing medicine and bringing new solutions to cancer patients in need."

KI scientists within NextGenNK will establish iPSC-derived NK-based therapeutic candidates utilizing Sorrento’s constructs and DAR technology. Work within KI has contributed to the development of methodologies that consistently generate robust and potent NK cell lineages following iPSC differentiation. Clinical trials of NK cell-based therapies for treatment of multiple myeloma led by researchers at KI have yielded promising preliminary results with long-lasting remissions. In a very cross-knit collaboration between Sorrento and KI, the team will aim to establish novel allogeneic, off-the-shelf, retargeted NK cell-based therapies.

Utilizing iPSCs enables mass production of off-the-shelf NK cell therapies that leverage Sorrento’s existing manufacturing infrastructure and know-how. Sorrento expects these validated re-engineered NK cell-based therapeutic candidates could potentially become a new generation in off-the-shelf treatments for cancer and infectious diseases. The core research will be performed at Karolinska Institutet with active involvement of the Sorrento R&D team in San Diego.

"The present collaboration brings together key competence from Sorrento and KI in an important area of cancer immunotherapy research. Sorrento’s intellectual contribution to the research at the Competence Center is a critical piece in enabling retargeted off-the-shelf NK cell products," said Evren Alici, Principal Investigator at KI.

"This is an important step in further enabling academic and industrial partnerships in the mission of achieving common goals for advancement of novel cancer immunotherapies," said Hans-Gustaf Ljunggren, Director of the NextGenNK Competence Center.

On June 4, 2021 Notable Labs Inc., a leader in technology-powered life science with a proprietary platform for predicting patient outcomes and accelerating precision drug development, reported top-line results from its clinical response prediction technology platform in a pediatric acute myeloid leukemia (AML) study to be presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting to be held June 4th-8th (Press release, Notable Labs, JUN 4, 2021, View Source [SID1234583542]). The data will be presented by Dr. Alexandra Stevens at Texas Children’s Cancer Center and highlights the correlation of functional drug sensitivity screening using Notable’s predictive technology platform with clinical outcomes of pediatric patients.

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In the exploratory study, blood or bone marrow samples from 22 de novo pediatric AML patients prior to receiving pre-induction chemotherapy were processed using Notable’s predictive technology platform. Chemosensitivity profiles across a broad spectrum of ex vivo conditions were analyzed and integrated into a predictive measure for individual patients. This measure of ex vivo drug sensitivity correlated with the patients’ clinical results of minimal residual disease and one year relapse-free survival.

"Our collaboration with one of the leading pediatric medical centers further demonstrates the potential of Notable’s prediction technology in identifying and fast-tracking combination therapies in a real-world situation." said Dr. Thomas Bock, CEO of Notable. Dr. Stevens added, "These results are a critical step forward towards our vision of precision medicine where treatments are focused on those patients who will clinically respond, especially for hard-to-treat patient populations."

Details of the presentation are as follows:

Poster Presentation

Title: Ex Vivo Drug Sensitivity Assay Correlates with Clinical Response in Pediatric AML
Session Name: Poster Session: Pediatric Oncology
Abstract Number: 10032
Presentation Time: Available beginning June 4th, 2021

On June 4, 2021 Vincerx Pharma, Inc. (Nasdaq: VINC) a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported the presentation of safety and efficacy data from the Phase 1 study of VIP152, the Company’s PTEFb/CDK9 inhibitor, in patients with double-hit lymphoma at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held virtually from June 4-8, 2021 (Press release, Vincerx Pharma, JUN 4, 2021, View Source [SID1234583541]).

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"The data generated in double-hit lymphoma are compelling, providing early evidence that on-target activity of VIP152 has the potential to provide durable responses in patients who have no standard of care therapy and poor prognoses," said Ahmed Hamdy M.D., Chief Executive Officer of Vincerx. "The achievement of durable metabolic complete responses with once weekly monotherapy lasting beyond two and three years is remarkable. These efficacy signals were also obtained with a favorable safety profile, with no patients stopping treatment due to adverse events, and the patients with metabolic complete responses stopping treatment only due to the COVID-19 pandemic. Our Phase 1 results, which also include durable disease control in solid tumors, provide a strong foundation of data, which support targeting MYC and MCL1-driven malignancies with our potent and selective PTEFb/CDK9 inhibitor. We look forward to further investigating the potential of VIP152 in challenging patient populations with our ongoing Phase 1b expansion study, which is currently enrolling patients with relapsed/refractory aggressive lymphoma and advanced solid tumors, and our soon to be launched Phase 1b dose-escalation in CLL relapsed/refractory to venetoclax and BTK inhibitors."

Key Presentation Highlights:

Poster presentation, titled, "Safety and efficacy of VIP152, a PTEFb / CDK9 inhibitor, in patients with double-hit lymphoma", include:

CDK9 mediates the transcription of oncogenes such as MYC and MCL-1, which play a critical role in a variety of cancers.
VIP152, a potent and selective inhibitor of CDK9, has completed dose escalation in patients with advanced malignancies (NCT02635672). Significant monotherapy clinical activity was observed with a favorable safety profile:
Seven patients with solid tumors had disease control during the dose escalation portion of the study, including a patient with pancreatic cancer (~14 cycles; dose 30 mg once weekly) and a patient with salivary gland cancer (~24 cycles; dose 22.5 mg once weekly).
One patient with double-hit DLBCL (DHL), who was treated with VIP152 30 mg once weekly, achieved metabolic complete remission. DHL is defined as a dual arrangement or overexpression of the MYC gene and either the B-cell lymphoma 2 (BCL2) or BCL6 genes.
No patients discontinued due to adverse events.
An expansion cohort of 6 additional patients with DHL were dosed with VIP152 30 mg once weekly:
All patients with DHL (median [range] age 70 [58-84] years) had received front-line R-CHOP or R-EPOCH, with two patients having had prior stem cell transplant, and additional therapies include R-DHAP, R-GemOx, R-ICE and durvalumab. Four patients had 2 prior lines of therapy and 3 patients had ≥3 prior lines of therapy. Three patients had been refractory to their last treatment. Six patients had advanced disease (Ann Arbor Stage III or IV) at study entry.
VIP152 had a favorable safety profile, with most common adverse events (AEs) being Grade 1 and Grade 2 severity. Two patients had a serious AE (Grade 3 syncope and Grade 3 tumor pain). No patients withdrew from treatment due to any AEs.
Pharmacodynamic biomarker analysis showed significant reduction, lasting at least 4 hours, of MYC, PCNA and MCL-1 mRNA in all patients.
Anti-tumor activity consisted of 2 metabolic complete responses (CRs) in 7 patients (29%), based on investigator-assessed FDG-PET scans.
Both metabolic CRs were durable, with patients remaining on treatment for 3.7 and 2.3 years until study withdrawal due to the COVID pandemic. Both patients had metabolic CRs at the time of study exit.
The results from this expansion cohort of 7 patients with DHL, a cancer known to have MYC translocations, suggests that reduction of MYC expression for at least 4 hours can provide durable complete remissions lasting several years. The favorable safety profile of VIP152 allowed for long-term dosing in elderly patients with advanced disease.
A Phase 1b expansion study in MYC-driven advanced cancers is ongoing, evaluating up to 30 patients with relapsed/refractory aggressive lymphoma, and up to 40 patients with advanced solid tumors.
The poster can be accessed on the presentations section of the Vincerx website.

On June 4, 2021 Aadi Bioscience, Inc. ("Aadi"), a privately-held clinical-stage biopharmaceutical company focusing on precision therapies for genetically-defined cancers with alterations in mTOR pathway genes, reported preliminary data from its lead investigational product candidate, FYARRO (sirolimus albumin-bound nanoparticles for injectable suspension; nab-sirolimus; ABI-009), during the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting being held virtually from June 4-8, 2021 (Press release, Aadi Bioscience, JUN 4, 2021, View Source [SID1234583540]). The poster is entitled "Institutional experience with nab-sirolimus in patients with malignancies harboring TSC1 or TSC2 mutations".1

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Dr. Mark Dickson, Principal Investigator of the study at Memorial Sloan Kettering Cancer Center stated, "I am encouraged by the activity of nab-sirolimus in multiple solid tumor histologies with TSC1 or TSC2 inactivating alterations. These new data provide strong rationale for conducting a broader investigation of nab-sirolimus in a tumor-agnostic setting. If the observed activity were reproduced, this could represent a meaningful advance in treatment for these patients."

Analysis from Expanded Access Patient Subset

Eight patients with malignancies and neoplasms bearing TSC1 or TSC2 inactivating alterations and representing histologies other than malignant PEComa were treated in a multi-institution expanded access program (NCT03817515) with FYARRO at 100 mg/m2 on day one and day eight of a 21-day cycle. RECIST v1.1 criteria were used for response analysis. Data cutoff occurred in March 2021.

Patients had a median of 3.5 lines of prior therapy and 6 of 8 patients were mTOR inhibitor-naïve. Treatment duration for all patients ranged from 0.7 to 12.0+ months. Five of 8 patients continued on treatment as of the data cutoff and 3 of 8 patients discontinued. Reasons for discontinuation were progressive disease (2 patients) and an adverse event (1 patient with acute kidney injury possibly secondary to administration of contrast).

Of the 8 patients treated, 7 patients were evaluable for response analysis and 1 patient progressed before the first scan. Five of 8 patients (63%, 95% CI: 25%-92%) achieved a confirmed partial response (PR). Amongst the patients who were mTOR inhibitor-naïve, 5 of 6 (83%, 95% CI: 36%-99+%) achieved a confirmed PR. Duration of response at data cutoff ranged from 3.1 to 9.7+ months and 3 of 5 responders continue on treatment.

Treatment-emergent adverse events that were ≥30% included edema, infections, mucositis, and pain (71% each), nail changes and vomiting (57% each), and hypertension and nausea (43% each). The majority of events were grade one or grade two. Treatment-related serious adverse events were reported in 2 patients and included hyperglycemia and infection; and acute kidney injury possibly secondary to administration of contrast. Three of 8 patients had a dose reduction from 100 mg/m2 to 75 mg/m2.

Dr. Neil Desai, founder and chief executive officer of Aadi, stated, "We are pleased to have provided FYARRO to patients through our expanded access program. Based on the data in this initial group of patients, and patients in the AMPECT trial with PEComa, we are planning to move forward with a tumor-agnostic registrational trial to confirm FYARRO’s activity in solid tumors with TSC1 or TSC2 inactivating alterations with planned initiation by the end of 2021."