On April 13, 2022 ChemoCentryx, Inc., (Nasdaq: CCXI), reported the presentation of preclinical data and initial pharmacokinetic (PK) and pharmacodynamic (PD) data from the ongoing Phase I clinical study of CCX559 during a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, ChemoCentryx, APR 13, 2022, View Source [SID1234612159]).

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The PD-L1/PD-1 interaction is one of the major immune checkpoints that limits the ability of effector T cells to destroy cancer cells. As a potential next generation therapy, an orally administered small molecule inhibitor of PD-L1 could have advantageous properties compared to approved monoclonal antibodies, such as better penetration into solid tumors, reduced immunogenicity, lack of Fc-mediated side effects and convenience of oral administration.

Preclinical characterization has demonstrated that CCX559 is a potent inhibitor of PD-L1 that blocks binding to PD-1 and CD80 and prevents PD-L1 inhibition of T cell activation. During 2021, ChemoCentryx initiated a first-in-human Phase I dose escalation study to evaluate the safety, tolerability, PK and PD of CCX559 in patients with various types of advanced cancer. In this Phase I basket study, CCX559 is taken orally once per day at specified dose levels, starting at 30 mg and ranging to date to 120 mg.

In the AACR (Free AACR Whitepaper) poster titled, CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors: Initial Pharmacokinetic and Pharmacodynamic Results from the in Progress First-In-Human Trial (abstract #4147), ChemoCentryx reported initial data available to date from patients enrolled in the first three dose cohorts in the ongoing Phase I study. Patients received CCX559 once daily at doses of 30 mg, 60 mg and 120 mg. All patients receiving 120 mg of CCX559 (n=9) were included in the PK evaluation reported in the poster. PD data for seven of the 120 mg patients (i.e., those whose data were available at time of submission) were also presented.

PK evaluation shows human CCX559 exposure is in line with preclinical projections. The mean exposure at 120 mg CCX559 in patients is comparable to exposures with anti-tumor activity in preclinical models and sufficient for PD-L1 target coverage, the half-life of the drug (enabling predicted once daily dosing) was also in line with projections.
PD activity results from the first cycle of treatment indicate that CCX559 is immunomodulatory. CD4 and CD8 T cell proliferation increased in all dose groups; soluble PD-L1 levels in plasma were significantly increased in the 120 mg patients by the end of the first cycle of dosing; and plasma IFNγ, CXCL9, CXCL10 were increased in the majority of patients assessed at 120 mg.
The PD activity of CCX559 is consistent with approved antibody inhibitors of PD-L1, in the extent and kinetics of the observed Th1 responses.
ChemoCentryx expects to present additional findings from this ongoing Phase I study at major oncology conferences through 2022. During the second half of 2022, the Company plans to advance CCX559 into a Phase Ib/II clinical trial to measure anti-tumor effects of CCX559 more directly.

On April 13, 2022 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a clinical-stage precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported positive topline results from the registrational TRIDENT-1 study across all four ROS1-positive advanced non-small cell lung cancer (NSCLC) cohorts, as reported by Blinded Independent Central Review (BICR) (Press release, Turning Point Therapeutics, APR 13, 2022, View Source [SID1234612158]).

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"We are very encouraged by the topline results from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 by BICR shared today and continue to believe repotrectinib is a potentially best-in-class drug candidate for patients with ROS1-positive advanced NSCLC," said Athena Countouriotis, M.D., President and Chief Executive Officer. "The confirmed ORR data and 95% confidence intervals across all four cohorts remain strong, and the initial estimated Kaplan-Meier landmark analyses based on limited median follow-up of approximately 10 months for both duration of response and progression free survival in the TKI-naïve population are trending in the direction we had hoped for given this is the highest area of unmet medical need. We believe a differentiated profile is built upon a strong ORR and durability of response that could improve upon the current standard of care."

The primary objective of the TRIDENT-1 study is to determine the cORR based on BICR as assessed by RECIST 1.1, and the key secondary objectives include duration of response (DOR), progression free survival (PFS) and intracranial activity. The dataset utilizes a February 11, 2022 data cutoff date. The safety analysis included 380 treated patients from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 across all cohorts, of which 287 patients were treated at the Phase 2 dose. The efficacy analyses included pooled patients from Phase 1 across all dose levels with an identified ROS1 fusion by next generation sequencing at baseline and Phase 2 patients. All patients received at least one dose of repotrectinib with at least four months of follow-up, and the majority of responders had at least six months of DOR follow-up.

Pooled Phase 1 and Phase 2 Topline Efficacy Analyses by BICR
ROS1-positive TKI-Naïve NSCLC (EXP-1; n=71 (8 from Phase 1 and 63 from Phase 2)):

In the ROS1-positive TKI-naïve advanced NSCLC population (EXP-1: n=71), the cORR was 79% (n=56/71; 95% CI: 68, 88), with 4 patients (6%) achieving a complete response (CR) and 52 patients (73%) achieving a partial response (PR). The cORR does not include one patient in an unconfirmed partial response (uPR) with tumor regression of -38% on the last scan, who remained on treatment awaiting the next scan as of the data cutoff date.

DOR ranged from 1.4+ to 35.1+ months with probability of patients in a response at 6, 9, 12 and 18 months reflected in Table 1 utilizing a Kaplan-Meier analysis, with a median duration of follow-up of 10.2 months.

Patients at Risk: Patients who have reached the specified timepoint without censoring or an event (progression or death).

PFS ranged from 0+ to 40.4+ months with probability of patients remaining progression free at 6, 9, 12 and 18 months reflected in Table 2 utilizing a Kaplan-Meier analysis, with a median duration of follow-up of 10.8 months.
Patients at Risk: Patients who have reached the specified timepoint without censoring or an event (progression or death).

ROS1-positive TKI-Pretreated NSCLC (EXP-2, EXP-3, and EXP-4; n=100):

In the ROS1-positive advanced NSCLC population pretreated with one prior TKI and prior platinum-based chemotherapy (EXP-2: n=26 (3 from Phase 1 and 23 from Phase 2)), the cORR was 42% (n=11/26; 95% CI: 23, 63), with 1 patient (4%) achieving a CR and 10 patients (38%) achieving a PR. Duration of response ranged from 3.6 to 18.3+ months.

In the ROS1-positive advanced NSCLC population pretreated with two prior TKIs without prior chemotherapy (EXP-3: n=18 (1 from Phase 1 and 17 from Phase 2)), the cORR was 28% (n=5/18; 95% CI: 10, 54), with 1 patient (6%) achieving a CR and 4 patients (22%) achieving a PR. Duration of response ranged from 1.9+ to 20.3+ months.

In the ROS1-positive advanced NSCLC population pretreated with one prior TKI without prior chemotherapy (EXP-4: n=56 (3 from Phase 1 and 53 from Phase 2)), the cORR was 36% (n=20/56; 95% CI: 23, 50), with 4 patients (7%) achieving a CR and 16 patients (30%) achieving a PR. The cORR does not include two patients with an uPR who both had tumor regressions of -47% on their last scans, both of whom remained on treatment awaiting their next scans as of the data cutoff date. Duration of response ranged from 1.9+ to 17.8 months.

Across the ROS1-positive TKI-pretreated advanced NSCLC population (EXP-2, EXP-3 and EXP-4), 17 patients had an identified ROS1 G2032R solvent front mutation detected, of which the cORR was 59% (n=10/17; 95% CI: 33, 82), with 1 patient (6%) achieving a CR and 9 patients (53%) achieving a PR. Duration of response ranged from 1.9+ to 20.3+ months.
TRIDENT-1 Topline Safety Analyses
Repotrectinib was generally well tolerated in a total of 380 patients with a safety and tolerability profile that was consistent with previously reported findings. The most commonly reported treatment emergent adverse event remained dizziness (61% all grade), of which 76% of patients who reported dizziness had a maximum severity of grade 1. The safety profile was comparable among the 287 patients who were treated at the Phase 2 dose.

As previously guided, the company anticipates discussing the topline BICR data with the U.S. Food and Drug Administration (FDA) at a pre-NDA meeting this quarter. The company plans to present detailed study results, including intracranial activity, from the ROS1-positive advanced NSCLC cohorts of the TRIDENT-1 study, at a medical conference in the second half of 2022.

Webcast/Conference Call Information
Turning Point will host a webcast and conference call on April 13, 2022 at 8 a.m. ET / 5 a.m. PT to discuss these results. Athena Countouriotis, M.D., President and Chief Executive Officer of Turning Point Therapeutics, will host the virtual event for investors and will be joined by Mohammad Hirmand, M.D., Chief Medical Officer. In addition, Alexander Drilon, M.D., Chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, will also be available on the call.

The event will be accessible through the "Investors" section of www.tptherapeutics.com or by dialing (877) 388-2118 (in the United States) or (470) 495-9489 (outside the U.S.) using conference ID 3197444. A replay will be available shortly after the live event through the "Investors" section of www.tptherapeutics.com.

On April 13, 2022 CDR-Life Inc., a biotechnology company pioneering a new and differentiated class of highly tumor-specific immuno-oncology therapeutics based on its proprietary antibody-based MHC-targeting T cell engager technology, reported the closing of a $76 million Series A financing led by Jeito Capital and RA Capital Management, with participation from Omega Funds (Press release, CDR-Life, APR 13, 2022, View Source [SID1234612155]). In connection with the financing, Rafaèle Tordjman, Founder & CEO of Jeito Capital, Daniel Marks, Principal of RA Capital, and Claudio Nessi, Managing Director of Omega Funds, will join the Company’s Board of Directors.

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CDR-Life is currently advancing its lead program, CDR404, a first of its kind dual MAGE-A4 T cell engager which targets solid tumors across multiple indications, based on the Company’s unique M-gager technology. Proceeds from the Series A financing will advance CDR404 through potential clinical proof-of-concept readout as well as expansion of the pipeline leveraging the Company’s M-gager technology for targeting intracellular antigens positioned to deliver unparalleled specificity and affinity in solid tumors.

"We are honored to have the support of these high-caliber investors, reflecting both the critical need for effective T cell engaging therapies against solid tumors and the support of the CDR-Life product engine and development pipeline," said Christian Leisner, PhD, Chief Executive Officer of CDR-Life. "The proceeds from this financing allow us to fund our first clinical proof-of-concept opportunity with CDR404, while continuing development of novel targeted immunotherapies based on CDR-Life’s superior T cell engaging platform. We are thankful to have the opportunity of raising a significant Series A round in such challenging times with an excellent European and US co-led investor group, assisting us in advancing our pipeline and goal of empowering cancer patients with uniquely targeted immunotherapies."

"We are thrilled to invest in CDR-Life which absolutely embodies our investment strategy with its high-quality science in T cell engagers, expert leadership team which has together already built a previous successful Biotech company, strong syndicate of investors and significant capital. Jeito Capital with this 10th investment is building a diversified portfolio of the next generation of European biotech leaders with a global reach in different therapeutic areas and development stages. CDR-Life is ideally positioned to accelerate its therapies based on innovative modalities for the benefit of millions of patients with limited therapeutic options. We look forward to support CDR-Life’s success," said Rafaèle Tordjman, Founder and CEO of Jeito Capital.

"CDR-Life has the deep biologics and platform technology expertise to rapidly develop bispecific molecules against this promising, but challenging, class of intracellular targets," said Daniel Marks, Principal of RA Capital. "We’re especially pleased to be working with these leading healthcare investors and this experienced and talented leadership team."

Based in Switzerland, CDR-Life is led by an experienced team of biotech executives who have developed new medicines and closed substantial biotech deals, including Beovu and ESBATech. The Company has an ongoing partnership with Boehringer Ingelheim, advancing its program, CDR202, into preclinical stage of development targeting macular degeneration. Clinical candidate, CDR101, a next generation BCMA, CD3, and PD-L1 targeting trispecific antibody in preclinical development for the treatment of multiple myeloma (MM) has recently demonstrated increased in vitro activity compared to clinical stage-like bispecific BCMA therapies, inducing superior T cell activation in bone marrow samples of MM patients and more durable tumor eradication in a mouse xenograft model. CDR101 is ready for IND-enabling studies.

On April 13, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that it has deprioritized further development of ONCT-216 to reallocate resources to zilovertamab, the Company’s investigational anti-ROR1 monoclonal antibody, and its Phase 3 registrational trial that the Company expects to initiate in Q3 2022 (Press release, Oncternal Therapeutics, APR 13, 2022, View Source [SID1234612154]). As such, the Company has discontinued enrollment in the Phase 1/2 study evaluating ONCT-216 in patients with relapsed or refractory Ewing sarcoma.

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"This asset prioritization allows us to further sharpen our focus on hematological malignancies and prostate cancer, while deploying our capital towards meaningful catalysts as we navigate this historically challenging pandemic, geopolitical and capital markets macroenvironment," said James Breitmeyer, MD, PhD, Oncternal’s President and CEO. "We believe this focused approach, along with prudent cash management, will enable us to fund our operations well into the third quarter of 2023, as we continue to explore all potential sources of capital to enable us to reach our milestones."

The Company expects to initiate its global registrational Phase 3 Study ZILO-301 in the third quarter of 2022, taking into account the impact of geopolitical factors and COVID-19 related supply chain issues. The study will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo, and all patients will continue receiving oral ibrutinib. The novel ZILO-301 design is supported by encouraging data from the Company’s ongoing Phase 1/2 clinical trial of zilovertamab plus ibrutinib for patients with MCL or CLL, as well as by a successful End-of-Phase-2 meeting with the U.S. Food and Drug Administration (FDA).

The Company’s lead autologous ROR1-targeted CAR-T cell therapy program candidate, ONCT-808, is advancing according to plan towards an Investigational New Drug (IND) application submission expected in mid-2022, based on supportive manufacturing and preclinical data as well as a productive pre-IND meeting with the FDA earlier this year.

Finally, the Company continues to advance ONCT-534, its lead candidate in its DAARI program, and expects to initiate IND-enabling GLP toxicology studies and GMP manufacturing later this quarter. ONCT-534 has shown anti-tumor activity in preclinical studies relevant to multiple clinically important forms of resistance for patients with prostate cancer, including those involving overexpression of the androgen receptor, or expression of mutants of the androgen receptor, or splice variants such as AR-V7.

About Zilovertamab (formerly Cirmtuzumab)
Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL or chronic lymphocytic leukemia (CLL), in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1 expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.

On April 13, 2022 Phosplatin Therapeutics Inc., a clinical stage pharmaceutical company focused on oncology therapeutics, reported the first patient has been treated in a Phase 2 clinical trial of the company’s lead therapeutic candidate, PT-112, in patients with recurrent thymic epithelial tumors (TETs), specifically thymoma and thymic carcinoma (Press release, Phosplatin, APR 13, 2022, View Source [SID1234612153]). The trial is being conducted under formal collaboration with the National Cancer Institute (NCI), part of the National Institutes of Health (see NCT05104736).

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The Phase 2 trial is designed to further assess the safety and efficacy of PT-112 in patients with thymoma and thymic carcinoma, and to use correlative studies to explore molecular profiles, examine parameters of immune activation and analyze immune cell infiltration in response to PT-112 treatment, as the candidate is known to promote immunogenic cell death (ICD). ICD is an immunostimulatory form of cancer cell death in the tumor microenvironment, and PT-112’s highly potent induction of ICD has been validated in relevant cancer models.

Phosplatin is providing NCI with PT-112 drug supply and support for correlative research, and NCI is overseeing enrollment and dosing of the study’s intended 53 patients. To be eligible for the study, patients must have uncommon tumors of the thymus (TETs) returned or progressed after treatment with at least one platinum-containing chemotherapy, or have refused standard treatment. The primary endpoint is overall response rate (ORR) per RECIST 1.1 criteria. The secondary endpoint measures include safety, duration of response, progression free survival, overall survival and ORR based on ITMIG-modified RECIST criteria (as established by the International Thymic Malignancy Interest Group).

"As an immunomodulatory treatment, PT-112 has performed well in early phase trials for TETs and warrants additional Phase 2 testing. Given the significant unmet need for patients with recurrent TETs, with no established immunotherapy option and no approved drug, it is important that we continue to study potential therapies," said Arun Rajan, MD, Senior Clinician in the Thoracic and GI Malignancies Branch at the NCI.

"In our Phase 1 trial of PT-112, we reported favorable safety data and observed a durable clinical response in a patient with advanced metastatic thymoma, which had the signature of potential immune involvement to the response," said Robert Fallon, Phosplatin President and Chief Executive Officer. "We are excited to work with Dr. Rajan and his outstanding team at the NCI to further study the potential of PT-112 to provide significant benefit to patients with these cancers."

Phosplatin holds an FDA Orphan Drug Designation for PT-112 in thymoma and thymic carcinoma. TETs, including thymomas and thymic carcinomas, are uncommon tumors of the thymus for which there is no FDA-approved drug. The five-year survival rate for patients with thymoma or thymic carcinoma is 55%. In cases of relapse following surgical intervention, TETs have the potential to metastasize and there are limited options for treatment.

About PT-112

PT-112 is the first small-molecule conjugate of pyrophosphate in oncology, and possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and now includes the Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal collaboration with the NCI. The PD-L1 combination Phase 2a study is ongoing in a dose confirmation cohort of non-small cell lung cancer (NSCLC) patients.