bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical evaluation of KZR-261, a novel small molecule inhibitor of Sec61.
Authors: Lowe Eric , Fan R. Andrea , Jiang Jing , Johnson Henry W. B. , Kirk Christopher J. , McMinn Dustin , Millare Beatriz , Muchamuel Tony , Qian Yu , Tuch Brian Benjamin , Whang Jennifer A. , Zuno Patricia
Published: May 2020

3582

Background: Secreted and transmembrane proteins play key roles in malignant transformation and growth, including in autocrine growth factor expression, receptor oncogene signaling, and immune system evasion. Biogenesis of these proteins involves translocation of the nascent polypeptides into the endoplasmic reticulum (ER) through the Sec61 channel, providing an untapped therapeutic target for a broad spectrum of malignancies. Here we describe preclinical activity of KZR-261 and related inhibitors of Sec61-dependent protein secretion. Methods: Sec61 inhibition with KZR-261 and related analog KZR-834 were evaluated using cell lines overexpressing proteins of interest tagged with luciferase. In vitro anti-tumor activity was assessed against a panel of 346 cell lines across 25 tumor types. Quantitative proteomic profiling by mass spec and gene expression profiling by RNAseq were conducted following treatment in multiple solid and heme tumor cell lines. Anti-tumor efficacy was evaluated in athymic nude mice implanted with the cancer cell lines H82 (SCLC), HT29 (CRC), BxPC3 (Pancreatic), 22RV1 (Prostate), H929 (Myeloma) and RL (NHL). Activity was also evaluated in a MC38 syngeneic colon tumor model. Results: KZR-261 and KZR-834 exhibited nanomolar potency against many therapeutic targets, including immune checkpoints, VEGF-A, VEGFR and EGFR. Broad in vitro anti-cancer activity was observed with KZR-834, which potently decreased cell viability across both solid and heme tumor types including CRC, Pancreatic, HNSCC, HCC, Lymphoma and Myeloma. Global proteomic analysis observed more than 1.5 fold downregulation of < 10% of detected Sec61 client proteins following treatment, while gene expression profiling revealed upregulation of ER stress response genes in sensitive versus resistant cell lines. Analysis of the TCGA database also found these genes upregulated in a number of different tumor types. In vivo, weekly IV administration was well tolerated and induced a dose dependent anti-tumor response at doses below the MTD in solid and heme xenograft models. In the syngeneic MC38 model, administration of KZR-834 in combination with anti-PD1 antibody resulted in greater anti-tumor activity than either single agent. Conclusions: Novel Sec61 inhibitors potently block expression of secreted and membrane proteins, translating into anti-tumor activity against many tumor types in vitro and in vivo, suggesting broad therapeutic potential. Clinical trials are being planned with KZR-261 to understand safety and early efficacy of this novel compound and therapeutic target.
Results of a completed phase I trial of CBL0137 administered intravenously (IV) to patients (Pts) with advanced solid tumors.
Authors: Sarantopoulos John , Mahalingam Devalingam , Sharma Neelesh , Iyer Renuka V. , Ma Wen Wee , Ahluwalia Manmeet Singh , Johnson Saramarie , Purmal Andrei , Shpigotskaya Polina , Hards Ann , Leonov Andrey , Gurova Katerina , Gudkov Andrei , Zakurdaeva Kristina , Miller Langdon L. , Dowlati Afshin
Published: May 2020

3583

Background: The novel curaxin CBL0137 intercalates into DNA, interfering with histone/DNA binding. Consequent trapping of histone chaperone FACT leads to MYC, NF-kB, and HSF1 inhibition, p53 activation, and an IFN response. CBL0137 shows broad nonclinical antitumor activity (Gasparian et al. Sci Transl Med. 2011; 3(95):95ra74). Methods: This dose-ranging study assessed the CBL0137 maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and CBL0137 safety, pharmacokinetics (PK), and efficacy in adults with advanced treatment-refractory solid tumors. CBL0137 was administered IV on Days 1, 8, and 15 of repeated 28-day cycles until progressive disease (PD) or unacceptable toxicity. Doses were escalated using a 3+3 design based on Cycle 1 dose-limiting toxicities (DLTs). PK was assessed through 168 hours after Day 1. Efficacy was evaluated every 8 weeks. Results: The study enrolled 83 pts (M/F [n] = 49/34; median [range] age = 64 [33-85] years; ECOG status [n] = 1/2 [32/51]), with cancer types (n) of colorectal (23), prostate (7), glioblastoma (6), liver (6), non-small-cell (5), and others (36) across 17 dose levels from 10 to 700 mg/m2/infusion. Durations of therapy ranged to 24 months. Cycle 1 DLTs (n type) were observed at 240 mg/m2 (1 Gr 3 photosensitivity), 400 mg/m2 (1 Gr 3 anemia), 700 mg/m2 (1 Gr 4 thrombocytopenia, 1 Gr 4 neutropenia/Gr 4 thrombocytopenia), and 650 mg/m2 (1 Gr 3 thrombocytopenia, 1 Gr 4 neutropenia/Gr 3 thrombocytopenia). Nausea and vomiting were successfully prevented with dexamethasone/serotonin antagonists. Photosensitization was effectively managed with sun protection. Peripheral venous thrombosis required central vein infusion in subjects with glioblastoma. PK showed dose-proportional increases in plasma CBL0137 area under the concentration-time curve (AUC), a high mean (range) volume of distribution (Vd) of 1,030 (655-1460) L/m2 consistent with extensive tissue distribution and DNA intercalation, and an average mean (range) half-life (t1/2) of 24.7 (10.3-40.7) hours without dose dependence. The best response was stable disease: 2 pts with liver cancer had tumor control for 9 and 24 months and a maximum tumor regression of 10%; 2 pts with prostate cancer had tumor regressions by 11% and 22%; 1 pt with uterine cancer had a 20% tumor regression. Conclusions: CBL0137 administered IV was generally well tolerated with manageable toxicities The MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. PK were predictable. Preliminary evidence of antitumor activity supports Phase 2 testing. Clinical trial information: NCT01905228 .
Activity of SY-5609, an oral, noncovalent, potent, and selective CDK7 inhibitor, in preclinical models of colorectal cancer.
Authors: Johannessen Liv , Ke Nan , Sawant Priyanka , Dworakowski Wojciech , D'Ippolito Anthony , Hu Shanhu , Rajagopal Nisha , Eaton Matthew , Hodgson Graeme
Published: May 2020

3585

Background: Colorectal cancer (CRC) is driven by genetic alterations that result in constitutive activation of oncogenic transcription factors (eg β-catenin, MYC) and of mitogenic signaling and cell cycle progression (driven by oncogenic mutations in KRAS and BRAF). CDK7 is a key regulator of transcription, through phosphorylation of the CTD domain of RNA Polymerase II, and of cell cycle progression, through phosphorylation of the cell cycle kinases CDK1, 2, 4, and 6. This dual role of CDK7 suggests inhibitors of CDK7 may be effective in the treatment of CRC. SY-5609 is an oral, noncovalent, potent and highly selective CDK7 inhibitor in phase 1 clinical development for patients with advanced solid tumors including CRC (NCT04247126). Here we report on the activity of SY-5609 in patient-derived xenograft (PDX) models of CRC. Methods: SY-5609 was administered once daily (QD) by oral gavage for 21 days (end of treatment, EOT) to mice bearing PDX models of CRC. The relationship between SY-5609 dose, pharmacodynamic (PD) changes in xenograft tissue, tumor growth inhibition (TGI), and mouse body weight (BW) was evaluated across a range of doses. SY-5609 TGI activity was also evaluated at sub-maximum-tolerated-dose levels across a panel of 30 independent CRC models including BRAF-, KRAS-, and non-BRAF/KRAS-mutant (wild type) models (n = 10 per group). Results: SY-5609 induced dose-dependent TGI in BRAF-mutant CRC PDX tumors, with tumor regressions observed at well tolerated doses (no BW loss at EOT), and no tumor regrowth for 2+ weeks after treatment was discontinued. Dose-dependent TGI was associated with dose-dependent PD changes in PDX tumor tissue. Across 30 PDX models, SY-5609 at well-tolerated doses (average BW loss of 0% at EOT across all models) induced ≥50% TGI in 67% (20/30) of models. Deep responses (≥90% TGI or regressions) were observed in 23% (7/30) of models, with enrichment for deep responses in BRAF mutant models (50%, 5/10) relative to KRAS mutant (10%, 1/10), and wild type (10%, 1/10) models. Conclusions: Daily oral dosing of the CDK7 inhibitor SY-5609 induces robust TGI, including regressions, in CRC PDX models at well-tolerated doses. Dose-dependent TGI is associated with dose-dependent PD changes in CRC PDX tumor tissue. These results highlight the therapeutic potential of SY-5609 in CRC and support the evaluation of SY-5609 in CRC patients in early phase clinical trials. SY-5609 is in phase 1 clinical development for patients with advanced solid tumors including CRC (NCT04247126).
AVID200, first-in-class TGF-beta 1 and 3 selective and potent inhibitor: Safety and biomarker results of a phase I monotherapy dose-escalation study in patients with advanced solid tumors.
Authors: Yap Timothy A , Lakhani Nehal J. , Araujo Daniel Vilarim , Rodon Ahnert Jordi , Chandana Sreenivasa R , Sharma Manish , Denis Jean-François , Gruosso Tina , Tremblay Gilles , O'Connor Maureen , Ghosh Ria , Sinclair Sandra , Wood Debra L. , Nadler Paul I. , Siu Lillian L.
Published: May 2020

3587

Background: AVID200 is a rationally designed first-in-class, selective inhibitor of transforming growth factor-beta (TGF-beta) that neutralizes TGF-beta 1 & 3 with pM potency and 4,000 fold selectivity over TGF-beta 2. TGF-beta 1 & 3 signaling has been associated with immune checkpoint inhibitor resistance and immunosuppression in the tumor microenvironment while TGF-beta 2 is required for normal cardiac function and hematopoiesis. Methods: NCT03834662 (AVID200-03) is a multicenter Phase 1 study following a standard 3 + 3 dose escalation to evaluate safety and tolerability of AVID200 given IV every 3 weeks to patients (pts) with advanced solid tumors. Peripheral target engagement was assessed in blood by ELISA and a cell-based functional assay, and in skin biopsies by immunohistochemistry (IHC). Pharmacodynamic markers of TGF-beta signal modulation and immune activation were evaluated in serum using the InflammationMAP v 1.0 (Myriad RBM) and in paired tumor biopsies by IHC and Imaging Mass Cytometry. Results: Nineteen pts (ECOG 0-1, median age 63 [range 39-77], 52.6% male) received AVID200 at 3 planned dose levels of 180 (N = 7), 550 (N = 6), and 1100 mg/m2 (N = 6) (~5, 15, and 30 mg/kg). The maximum tolerated dose was not reached. Three Grade (G) 3 treatment-related adverse events (TRAEs) were reported in 2 pts (diarrhea and lipase elevation, anemia); no > G3 TRAEs were observed. Serum exposure was dose-proportional and AVID200 sequestered all active TGF-beta 1 & 3, but not beta 2, in blood across the entire dosing period at all dose levels, providing proof-of-mechanism of AVID200. SMAD2 phosphorylation in skin biopsies was detectably reduced on Day 4 at 15 and 30 mg/kg. Pro-inflammatory markers in serum were increased on Day 8 versus baseline in a dose-dependent manner. Tumor biopsies of pts treated at 15 mg/kg showed modulation of TGF-beta signaling and immune activation. A best response of RECIST stable disease > 12 weeks was observed in 2 pts: 1 with adenoid cystic carcinoma (5 mg/kg; 8.7 months); 1 with breast carcinoma (30 mg/kg; 3.1 months). Conclusions: AVID200 was safe and well tolerated at dose levels of 5-30 mg/kg, with peripheral target engagement across the entire dosing period. AVID200 led to TGF-beta target modulation and immune activation. These data provide proof-of-principle that AVID200-mediated selective and potent inhibition of TGF-beta 1 & 3 is feasible in the clinic. The AVID200 monotherapy data warrant exploration of rational combination with a PD-(L)1 inhibitor. Clinical trial information: NCT03834662 .
Selpercatinib (LOXO-292) in patients with RET-mutant medullary thyroid cancer.
Authors: Shah Manisha H. , Sherman Eric Jeffrey , Robinson Bruce , Solomon Benjamin J. , Kang Hyunseok , Lorch Jochen H. , Worden Francis P. , Brose Marcia S. , Leboulleux Sophie , Godbert Yann , Meurer Marie , Morris John C. , Owonikoko Taofeek Kunle , Tan Daniel Shao-Weng , Gautschi Oliver , Patel Jyoti D. , Yang Luxi , Kherani Jennifer , Cabanillas Maria E. , Wirth Lori J.
Published: May 2020

3594

Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-mutant medullary thyroid cancer (MTC). Methods: Patients with RET-mutant MTC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 55 consecutively enrolled patients previously treated with multikinase inhibitors cabozantinib and/or vandetanib. Patients naïve to cabozantinib and vandetanib treatment were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of prior cabozantinib and/or vandetanib-treated patients with MTC (n = 55), the ORR by investigator assessment was 62% (95% CI 47.7–74.6, n = 34/55) and the median DoR was not reached (95% CI 18.4 months–not estimable) despite a median follow-up of 14.8 months. In cabozantinib/vandetanib treatment-naïve patients (n = 88), the ORR by investigator assessment was 69% (95% CI 58.6–78.7, n = 61/88, including 2 responses pending confirmation). Of the 59 confirmed responding patients, with a median follow-up of 8 months, responses were ongoing for 57 responders at the time of the analysis. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib use was associated with marked and durable antitumor activity in prior cabozantinib and/or vandetanib-treated patients and in cabozantinib/vandetanib-naïve patients with RET-mutant MTC, with the majority of responses ongoing in both cohorts. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .
Prophylactic dihydropyrimidine dehydrogenase (DPYD), and reactive cytidine deaminase (CDA) testing is feasible and reduces severe toxicity in Irish patients receiving 5-fluorouracil (5-FU) based chemotherapy.
Authors: Murphy Jake
Published: May 2020

3600

Background: 5-Fluorouracil (5-FU) steady state concentrations can vary up to fourfold among cancer patients. 5-FU intolerance and toxicity is associated with reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD) due to polymorphisms of the DPYD gene, as well as mutations in cytidine deaminase (CDA). Since 2012, Bon Secours Hospital, Cork has implemented prophylactic DPYD screening to reduce toxicity. Methods: In this retrospective cohort study, 742 adult cancer patients who underwent reactive or prophylactic DPYD testing in our center between 2012 and 2019 were included. Reactively tested patients were screened prior to 2012. 5-FU related toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) and analysed. Frequencies of polymorphisms in DPYD, affecting 5-FU metabolism in patients who experienced severe toxicity are described, in both patients who were retrospectively tested, and in our larger prophylactic patient cohort. Mutations of genes encoding CDA were also analysed. Analysis of type and severity of toxicity, and survival analysis will be presented at the Annual Meeting. Results: 742 patients were tested for DYPD in our centre, of which 704 were prophylactic tests. 11.4% of the patients tested prophylactically were found to have polymorphisms in the DYPD gene. Expectedly, a higher proportion of patients tested reactively were found to have polymorphisms in DYPD (21.9%). 21 out of 34 patients who had severe toxicity had CDA mutations present on testing. Further data involving classification and severity of toxicities, along with survival analysis will be presented at the Annual Meeting. Conclusions: The prevalence of DPYD mutations in Ireland is estimated to be 7-10%, and is putatively responsible for approximately 20% of all severe 5-FU toxicities suffered by cancer patients. Implementing prophylactic DPYD screening is beneficial in reducing toxicities in this setting. Future work will focus on phenotypic measurements of uracil metabolism and pharmacokinetic 5-FU monitoring to further reduce toxicity in patients who do not have DPYD mutations.
A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.
Authors: George Ben , Richards Donald A. , Edenfield William Jeffery , Warner Steven L , Mouritsen Lars , Bishop Reyna , Anthony Stephen Patrick , Bearss David , Vogelzang Nicholas J. , Whatcott Clifford
Published: May 2020

3611

Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .
Single-agent ONC201 in recurrent H3 K27M-mutant diffuse midline glioma.
Authors: Arrillaga-Romany Isabel , Kurz Sylvia Christine , Tarapore Rohinton , Sumrall Ashley , Butowski Nicholas A. , Harrison Rebecca A. , De Groot John Frederick , Chi Andrew S. , Shonka Nicole A. , Umemura Yoshie , Odia Yazmin , Mehta Minesh P. , Nghiemphu Phioanh Leia , Cloughesy Timothy Francis , Lu Guangrong , Oster Wolfgang , Allen Joshua E. , Batchelor Tracy , Lassman Andrew B. , Wen Patrick Y.
Published: May 2020

3615

Background: Recurrent H3 K27M-mutant diffuse midline glioma is a lethal brain tumor that predominantly affects children and young adults and has no effective therapy. ONC201 is a first-in-class orally administered, anti-cancer small molecule that selectively antagonizes the dopamine receptors DRD2/DRD3 and agonizes ClpP, a mitochondrial protease. Prior studies have indicated dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Methods: Adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II clinical trial (NCT02525692), and expanded access protocols under the Sponsor’s IND. Results were pooled among patients treated with ONC201 monotherapy through any of these trial with H3 K27M confirmed glioma, progressive and measurable disease by RANO, > 90 days from completion of prior radiation, no evidence of leptomeningeal dissemination, midline location other than primarily pons or spinal cord, and baseline KPS > 60. Using an enrollment cutoff of February 15, 2019 and data cutoff of July 31, 2019, there were 20 patients (NCT03295396, 12; NCT02525692, 7; expanded access, 1). Dosage was 625 mg weekly in 19 and once every 3 weeks in 1. Results: No DLTs or treatment discontinuations due to toxicity occurred. Midline gliomas can exhibit minimal contrast enhancement or exhibit a mixture of contrast-enhancing and non-contrast enhancing regions in the tumor. As a result, blinded independent central review (BICR) of tumor response by MRI was assessed by RANO-HGG and RANO-LGG for each patient to capture contrast-enhancing lesions by T1 post-contrast and non-contrast-enhancing assessments by T2/FLAIR, respectively, in the object response rate. The best response by RANO-HGG or RANO-LGG is 30% (95% CI, 11.9-54.3%). Duration of response by RANO-HGG is median 52.7 weeks (range 15.9-138.3). One patient with stable disease as of this data cutoff has continued on treatment beyond 12 months and recently underwent an investigator-reported PR by RANO-HGG that is pending confirmation. Conclusions: Single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M-mutant diffuse midline glioma patients. Clinical trial information: NCT03295396, NCT02525692 .
The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models.
Authors: Drilon Alexander E. , Zhai Dayong , Rogers Evan , Deng Wei , Zhang Xin , Ung Jane , Lee Dong , Rodon Laura , Graber Armin , Zimmerman Zachary Franklin , Murray Brion W , Subbiah Vivek
Published: May 2020

3616

Background: RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391).
Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma.
Authors: Kawakibi Abed Rahman , Tarapore Rohinton , Gardner Sharon L. , Kurz Sylvia Christine , Wen Patrick Y. , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas A. , Sumrall Ashley Love , Shonka Nicole A. , Harrison Rebecca A. , De Groot John Frederick , Mehta Minesh P. , Odia Yazmin , Hall Matthew David , Cloughesy Timothy Francis , Ellingson Benjamin M. , Umemura Yoshie , Allen Joshua E. , Koschmann Carl Johannes ,   Koschmann Lab, Oncoceutics Team
Published: May 2020

3617

Background: Diffuse midline gliomas, H3 K27M-mutant are associated with a poor prognosis compared to H3 wild-type gliomas and have no effective therapy following first-line radiation. ONC201 is a bitopic DRD2 antagonist and allosteric ClpP agonist that has shown encouraging single agent efficacy in recurrent H3 K27M-mutant gliomas located in various midline structures of the brain. In addition to tumor and immune cells, the pharmacodynamics of ONC201 extend to stromal cells that can mediate a bystander antitumor response in preclinical models. Given this observation and that the thalamus has the highest extrastriatal expression of DRD2, we report the clinical experience of ONC201 in a subgroup of H3 K27M-mutant glioma patients with primary tumors located in the thalamus. Methods: We analyzed 29 thalamic H3 K27M-mutant glioma patients treated with ONC201 in clinical trials enrolled as of 5/22/19. Nineteen enrolled with recurrent disease whereas 10 enrolled following radiation prior to recurrence. Twelve patients enrolled on NCT03295396, 10 NCT03416530, 4 NCT02525692, and 3 expanded access. Median age was 22 years old (range: 5-70) and baseline KPS was 80 (range: 60-90). Median time from radiation to start of ONC201 was 1.8 months (range: 0.2-8.7) for non-recurrent patients and 7.2 months (range: 1.4-102.0) for recurrent patients. Results: As of 12/18/2019, PFS6 and OS12 measured relative to initiation of ONC201 are 26.3% and 36.8%, respectively, in the recurrent group. For patients initiating ONC201 post-radiation prior to recurrence, median PFS or OS have not been reached with a median follow up of 21.9 months (8.6-26.6) from diagnosis, which surpass historical OS of 13.5 months. Best response for evaluable recurrent patients by RANO: 1 CR, 3 PR, 4 SD, 8 PD, 3 not reported; for non-recurrent patients: 2 PR, 4 SD, 1 PD, 3 not reported. Median duration of response for recurrent patients is 14.0 months (2.0-33.1). ONC201 was well tolerated and no dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. Conclusions: In summary, single agent ONC201 administered at recurrence or following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients. Investigations are ongoing to assess whether micro-environmental DRD2 expression correlates with responses of thalamic H3 K27M-mutant glioma to ONC201. Clinical trial information: NCT03295396, NCT03416530, NCT02525692 .
ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPG.
Authors: Gardner Sharon L. , Koschmann Carl Johannes , Tarapore Rohinton , Allen Jeffrey C. , Zaky Wafik Tharwat , Odia Yazmin , Hall Matthew , Daghistani Doured , Khatib Ziad , Aguilera Dolly , MacDonald Tobey J. , Fouladi Maryam , McGovern Susan Lynne , Kline Cassie , Vitanza Nicholas A , Lu Guangrong , Oster Wolfgang , Allen Joshua E. , Khatua Soumen
Published: May 2020

3619

Background: ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that has demonstrated promising activity in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 in recurrent H3 K27M-mutant glioma patients . The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients as well tolerated and biologically active. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center trial for pediatric H3 K27M-mutant glioma or non-biopsied DIPG employed a 3+3 dose-escalation and dose-expansion design with 6 arms. Arms A and E, which have completed accrual, determined the RP2D of ONC201 using oral capsule and liquid formulations in post-radiation pediatric H3 K27M-mutant glioma patients ONC201, respectively. Arm B aims to determine the RP2D for ONC201 in combination with radiotherapy in patients with newly diagnosed DIPG. Arms C and D aim to measure intratumoral ONC201 concentrations in midline glioma patients and the impact of ONC201 on H3 K27M DNA levels in CSF, respectively. Arm F was recently opened to study ONC201 as a single agent in patients with progressive H3 K27M-mutant tumors (excluding DIPG and spinal cord tumors) following radiotherapy. After determining the RP2D, a dose-expansion cohort will evaluate the safety, radiographic response, and activity of ONC201. Results: An RP2D of weekly 625mg ONC201 scaled by body weight as a capsule or in liquid formulation was established in the primary endpoints of arms A, B and E alone or in combination with radiation, without incidence of dose-limiting toxicity (DLT). Pharmacokinetic profiles were similar to those observed in adults (T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL), with similar exposure across body weights. Conclusions: ONC201 was well tolerated without DLTs at the same adult RP2D scaled by body weight as monotherapy or in combination with radiotherapy in pediatric H3 K27M-mutant glioma patients. Further investigation of ONC201 to treat H3 K27M-mutant glioma and DIPG is warranted. Clinical trial information: NCT03416530 .
Therapeutic vulnerabilities among KRAS G12C mutant (mut) advanced cancers based on co-alteration (co-alt) patterns.
Authors: Nusrat Maliha , Roszik Jason , Holla Vijaykumar , Cai Tiantian , Hong Meiyue , Coker Oluwadara , Johnson Benny , Rodon Ahnert Jordi , Janku Filip , Kopetz Scott , Shaw Kenna Rael , Meric-Bernstam Funda , Hong David S.
Published: May 2020

3625

Background: Oncogenic KRAS mut drive cancers and confer therapeutic resistance by activating MAPK signaling. Inhibiting KRAS has been elusive until the recent promising phase I trials with KRAS G12C inhibitors (i). We characterized frequencies of KRAS G12C mut and gene co-alt among advanced cancer patients (pts) to identify therapeutic vulnerabilities for combination development. Methods: We analyzed next generation sequencing datasets from MD Anderson Cancer Center (MDACC, n = 42,316) and AACR GENIE (n = 56,970). Genes and individual alterations were annotated for potential actionability with approved or investigational drugs and grouped into 12 oncogenic pathways. Frequencies of potential drug combinations with KRAS G12Ci were estimated per tumor type based on co-occurrence of potentially actionable alterations. Results: KRAS G12C was present in 850/34,801 (2.4%) advanced solid tumor and 22/7698 (0.3%) hematologic malignancy pts in MDACC dataset; and 1422 (2.5%) pts in AACR GENIE. Among solid tumor pts, 798 had histology data and 640 had ≥46 gene profiling. Most common cancers were non-small cell lung (NSCLC, 67%), colorectal (CRC, 24%), other gastrointestinal (oGI, 4%) and gynecologic (gyn, 2%). KRAS G12C prevalence was 19.5% (441/2265) in NSCLC and 4.2% (146/3469) in CRC. Genes most commonly co-altered were TP53 (42%), STK11 (17%) and MET (11%) in NSCLC; TP53 (58%), APC (54%) and PIK3CA (24%) in CRC; TP53 (42%), APC (21%) and ATM (21%) in oGI; TP53 (56%), PIK3CA (25%), and PTEN (19%) in gyn cancers. These co-alt did not impact overall survival. In both datasets, as compared to KRAS wild, KRAS G12C was significantly co-altered with STK11 in NSCLC; PIK3CA and SMAD4 in CRC (P < 0.05 for all). EGFR mut in NSCLC and BRAF mut in CRC rarely co-occurred with KRAS G12C (P < 0.01). Most frequently co-altered oncogenic pathways in NSCLC, CRC, oGI and gyn cancers respectively included PI3K (27, 32, 33, 44 %), receptor tyrosine kinases (13, 16, 42, 13 %) and DNA damage repair (12, 10, 38, 19 %). Potentially actionable co-alt frequencies suggest that combining KRAS G12Ci with mTORi or PI3Ki would be indicated most frequently, in 24% and 13% of all pts respectively. Conclusions: KRAS G12Ci development is most relevant for NSCLC, gastrointestinal and gyn cancers. The co-alt patterns highlight relevant oncogenic pathways and candidate drugs for future combination therapies. Co-inhibition of PI3K-mTOR and MAPK pathways has shown synergism in prior pre-clinical studies but had poor tolerance in pts. There is opportunity to revisit this approach with the new KRAS G12Ci.
Employing RNA sequencing to enhance treatment options for cancer patients.
Authors: Basu Gargi D. , LoBello Janine , Ozols Audrey
Published: May 2020

3628

Background: Fusions and translocations account for 20% of cancer mortality globally. Maximizing their detection enhances the utility of precision medicine for various solid and hematologic cancers. Practice guidelines stress the importance of RNA sequencing. Novel assay techniques employing a comprehensive genomic profiling approach, including RNA sequencing, yield information beyond conventional DNA next generation sequencing (NGS) alone. Methods: Tumor samples (N = 1517) were assayed combining whole transcriptome (RNA) sequencing, whole exome (DNA) sequencing, and comparison of tumor sequence vs. paired normal DNA. Results were analyzed to determine the frequency of rare and common RNA fusion and variant detection. Findings were mapped to a knowledge-base of targeted treatment options. Results: Analysis detected 79 (5.2%) actionable fusions and 15 (1%) transcript variants across major solid and heme-based malignancies. Notably, we observed actionable transcript variants that are not detectable at the DNA level including: EGFRvIII, EGFRvIVa and EGFRvIVb in GBM; ARv7 in prostate, and METe14 in TNBC. Many fusion cases (42%, n = 33) had no other actionable molecular abnormalities. Novel fusions included: SLC12A/ROS1 in low-grade spindle cell neoplasm with myogenic differentiation, KANK1/NTRK2 in ganglioneuroblastoma, ETV6/NTRK3 in metastatic mammary analogue secretory carcinoma, FGFR1/SCT in germ cell tumor, ZNF33B/RET fusion in GBM, SH3BP4/ERBB4 and EML4/ALK in RCC, VTCN1/NRG1 in pancreatic cancer, and AGRN/NRG1 in cholangiocarcinoma. More common actionable fusion events included: EML4/ALK in NSCLC, KIAA1549/BRAF in pilocytic astrocytoma, FGFR2 and FGFR3 in cholangiocarcinoma and urothelial cancers and ESR1 in endocrine therapy-resistant breast cancers. The fusion events detected in heme-based malignancies included MLLT10 and MLLT4 in AML, BCR/ABL in leukemias, TCF3/PBX1 in B cell ALL, NPM1/ALK in ALCL, and novel fusion CIITA/CD274 in DLBCL. All RNA fusions and transcript variants found were matched to FDA-approved or investigational treatment options. Conclusions: Maximizing the rate of variant detection for targeted therapy relies on precise identification of common and rare fusion events. Without the addition of RNA sequencing, 15 transcript variants in our cohort would have been missed and 33 of the fusions may have gone undetected by conventional DNA NGS testing, resulting in zero targeted treatment options for this vulnerable population. Further use of comprehensive genomic profiling is vital to optimizing cancer care.
Identifying functional loss of ATM gene in patients with advanced cancer.
Authors: Pilie Patrick Glen , Gheeya Jinesh S. , Kyewalabye Keith , Goswamy Rohit Vivek , Wani Khalida M , Le Hung , Campbell Erick , Sanchez Nora Sylvia , Yang Dong , Garmezy Benjamin , Ileana Dumbrava Ecaterina Elena , Rodon Ahnert Jordi , Heffernan Timothy , Holla Vijaykumar , Shaw Kenna Rael , Meric-Bernstam Funda , Lazar Alexander J. , Wang Wei-Lien , Yap Timothy A
Published: May 2020

3629

Background: ATM is frequently mutated in cancer, and defects may serve as a putative predictive biomarker. However, the functional impact of most ATM variants is not well known. In this study, we examined the relationship between ATM variants and ATM protein expression to better discern ATM functional defects in patients (pts) with advanced cancer. Methods: We retrospectively identified pts seen at MD Anderson Cancer Center who had ATM variants detected on CLIA-certified next generation sequencing (NGS) assays. ATM immunohistochemistry (IHC) was performed on available tumors. We then prospectively assessed ATM IHC on tumors from pts who were referred for DNA damage repair inhibitor (DDRi) trials. Functional classification of the variants was performed via published in silico tools and/or precision oncology decision support (PODS). An IHC cut-off of 100% loss in tumor cell nuclei defined ATM loss of protein (LOP). Results: Of 1394 ATM-mutant tumors identified retrospectively, ATM alterations were classified as 16% (N = 216) inactivating, 12% (N = 163) potentially inactivating, 71% (N = 993) variant of unknown significance (VUS), and 2% (N = 22) benign. Coding variants were seen across the ATM exonic structure/splice sites, and 20 individual variants were shared in > 10 pts. 263/297 available retrospective tumor samples had interpretable IHC results; 27% (N = 72) had ATM LOP. LOP was most prevalent in tumors with inactivating ATM variants (39/100, 39%); but, importantly, LOP was seen in 20% (N = 33/162) of potentially inactivating/VUS, thus better clarifying their functional impact. In the prospective cohort of 217 pt tumors, 17% (N = 37) had ATM LOP. 29% (N = 62/217) of this cohort also had ATM variants. ATM LOP was seen in 48% of tumors with inactivating variants (N = 14/29), 25% of tumors with potentially/VUS(N = 9/36), and 9% (N = 14/156) of tumors without ATM variants identified. ATM LOP was detected most commonly in colorectal (24%; N = 8/34), cholangiocarcinoma (20%; N = 6/30), prostate (16%; N = 16/104) and pancreatic (9%; N = 1/11) cancers among this cohort of pts referred for DDRi trials. Conclusions: ATM coding variants occurred across the gene, with certain variants shared across tumor types. The functional impact of most ATM variants was VUS, and ATM LOP can help clarify function in up to 25% of these VUS. Also, ATM LOP can be seen even in tumors without ATM variants identified, suggesting epigenetic or post-translational loss. Future prospective studies assessing predictive capability of paired DNA and protein-level profiling of ATM are warranted.
Predictive value of a CLIA-approved organoid based drug sensitivity test.
Authors: Margossian Astrid , Richardson Annie , Churchill Michael , Schaub Franz , Rosati Rachele , Appleyard Lauren , Pollastro Madison , Katabian Carolina , Motamedi Kathleen , Diaz Robert , Pereira Shalini , Kemp Christopher , Gadi Vijayakrishna K. , Grandori Carla
Published: May 2020

3630

Background: Precision medicine integrates genetic, molecular, and clinical information to optimize therapy selection for cancer patients. Ex vivo drug testing has the potential to match the right drug to the right patient. We developed a CLIA-certified functional drug assay for all solid tumors which provides an actionable report of organoid sensitivity to targeted, endocrine and chemotherapy agents as a tool for therapeutic decisions. Objectives: To establish the predictive power of the test in relation to well-known genomic biomarkers as well as prior treatments to identify drug sensitivity. To demonstrate that functional drug testing increases the actionability of genomic reports. Methods: From 2016 to 2019, 240 organoids from cancer patients were subjected to functional testing at SEngine Precision Medicine. Patients with advanced primary or metastatic cancer (solid tumors) who were treatment naïve or had previous therapies fail. Fresh samples of tumor cells from core biopsies, surgical excisions, or fluids arrived <48 hrs following collection and were cultured as 3D organoids. They were evaluated using a multi-dose response format with a library of up to 130 compounds. Drug sensitivity was quantified using a score that combines sensitivity and personalization of each patient’s response relative to a reference population. Known genomic actionability from levels of evidence 1-2 from MSKCC OncoKB were queried against results for correlation. Results: Organoids were derived from breast (18.7%), ovarian (18.3%), colorectal (17.9%), pancreatic (6.7%), and others solid tumors (38,3%). Median age of patients was 53 (r5-83). 68 drugs on average were tested per patient with a mean turnaround time of 18 days (r9 -37). A mean of 7 drugs per patient were identified as top scoring drugs. In 75 patients with genomic data, we found high concordance of drug sensitivity with known genomic anchors (e.g., inhibitors of BRCA1/ PARP, ERBB2/HER2, FGFR1-2/FGFR, KRAS, PIK3CA/PI3K), measured as sensitivity to drugs among this targeted groups. However, several patient samples demonstrated sensitivity to targeted agents in the absence of known genomic biomarkers. Most important, analysis of previous treatments indicated >90% of retrospective concordance. Conclusions: Organoid based drug testing exhibits strong concordance with genomic and retrospective clinical evidence. In addition, functional testing identifies candidate therapies in patients with no known biomarkers and can identify the significance of variants currently not validated.
Pooled safety analysis of single-agent lurbinectedin versus topotecan (Results from a randomized phase III trial CORAIL and a phase II basket trial).
Authors: Leary Alexandra , Gaillard Stephanie , Vergote Ignace , Trigo Jose , Kahatt Carmen Maria , Nieto Antonio , Fernandez Cristian Marcelo , Cullell-Young Martin , Zeaiter Ali Hassan , Subbiah Vivek
Published: May 2020

3635

Background: Lurbinectedin (L), an inhibitor of active transcription, has shown activity in second-line (2L) small cell lung cancer (SCLC) (ASCO 2019). Topotecan (T) is the only approved drug in 2L SCLC and is also used in platinum resistant ovarian cancer (PROC). Methods: This pooled safety analysis includes data from 554 patients (pts) treated with L at 3.2 mg/m2 Day 1 q3wk 1-h (no primary prophylaxis with G-CSF required): 335 with selected solid tumors (9 indications, including 105 pts with SCLC) from a phase II Basket study and 219 with PROC in the phase III CORAIL study. An indirect exploratory comparison (pooled data from CORAIL + Basket) and a direct comparison (data from CORAIL) of L vs. T are presented. Results: Most common adverse events with L were grade 1/2 fatigue, nausea and vomiting. Treatment-related (L/T): dose reductions: 22.9/48.3%, delays: 25.8/52.9%, grade ≥3 serious adverse events (SAEs): 15.0/32.2%, discontinuations: 3.2/5.7%, deaths: 1.3/1.5%, G-CSF use: 23.8/70.1%, and transfusions: 15.9/52.9%. Conclusions: Lurbinectedin has a predictable and manageable safety profile. A significant safety advantage was observed when lurbinectedin was compared with topotecan in the CORAIL trial in terms of hematological toxicities. With the limitations of indirect comparisons, in the pooled safety analysis, fewer lurbinectedin-treated pts had severe hematological toxicities, SAEs, dose adjustments, treatment discontinuations and use of supportive treatments than topotecan-treated pts. Clinical trial information: NCT02421588 and NCT02454972 . [Table: see text]
Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.
Authors: Janku Filip , Elez Elena , Iyer Gopa , Yamamoto Noboru , Tan Daniel Shao-Weng , Stathis Anastasios , Stammberger Uz M. , Evans Helen , Seroutou Abdelkader , Mais Anna , Schuler Martin H.
Published: May 2020

3640

Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .