Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2574-2574 ◽  
Author(s):  
Jeffrey R. Infante ◽  
Philippe L. Bedard ◽  
Geoffrey Shapiro ◽  
Todd Michael Bauer ◽  
Amy Prawira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
In Vivo Models ◽  
Best Response ◽  
Gastrointestinal Side Effects ◽  
Anti Tumor Activity

2574 Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.

Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13524-e13524
Author(s):  
S. M. Rudman ◽  
C. Comins ◽  
D. Mukherji ◽  
M. Coffey ◽  
K. Mettinger ◽  
...  
Keyword(s):  
Phase I ◽  
Biological Effects ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Systemic Delivery ◽  
Open Label ◽  
Phase Ii Studies

e13524 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras. Wild- type reovirus serotype 3 Dearing strain (Reolysin) has selective antitumor activity in vitro, in murine models, and after systemic delivery in humans in phase 1 trials. Synergistic tumour kill has been observed combining reovirus with taxanes in a range of cancer cell lines and in vivo. Methods: Patients were treated in an open-label, dose-escalating, phase I trial and received 3- weekly 75mg/m2 docetaxel i.v. and reovirus i.v. (day 1–5 of first week inclusive). Reovirus was administered at a starting dose of 3x109 tissue culture infectious dose (TCID50) and then increased to 1 x 1010 and 3 x 1010 TCID50. Primary endpoints were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to recommend a dose and schedule for future investigation. Secondary endpoints were to evaluate pharmacokinetics, neutralizing antibody development, cell- mediated immune response and anti-tumour activity. Results: 17 patients were treated (15 males, median age 60 years). No MTD has been reached. DLT's observed were G4 neutropenia (and a recurrent perianal abcess) and G3 rise in AST. Other toxicities observed were fatigue, hypotension and neutropenic sepsis. At present, 5 patients remain on treatment. We have observed 2 partial responses (breast and gastric carcinoma) and 10 patients had stable disease as best response. Conclusions: Reovirus is well tolerated when administered in combination with intravenous docetaxel, with predictable toxicity observed. The recommended dose has been defined at 3x1010 TCID50 and phase II studies are planned. Objective radiological evidence of anticancer activity for this combination has been observed. [Table: see text]

BBI608-224: A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) administered with panitumumab in KRAS wild-type patients with metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 677-677 ◽  
Author(s):  
Tim Larson ◽  
Waldo Feliu Ortuzar ◽  
Tanios S. Bekaii-Saab ◽  
Carlos Becerra ◽  
Kristen Keon Ciombor ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase 1 ◽  
Open Label ◽  
Cancer Stemness ◽  
Anti Cancer ◽  
Previously Treated ◽  
Multi Center Study ◽  
Anti Tumor Activity

677 Background: Napabucasin a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. In a phase 1 study, napabucasin monotherapy was well tolerated with encouraging signs of anti-tumor activity at the RP2D of 500 mg BID. Methods: The current open-label, multi-center study includes phase II expansion in pts with refractory, K- Raswt mCRC to confirm safety and anti-tumor activity of napabucasin administered orally at 480mg BID in combination with panitumumab (6mg/kg bi-weekly). Results: 72 pts were enrolled, 48 pts were evaluable by RECIST of which 7 (15%) and 41 (85%) had 2 or >3 prior treatment lines, respectively. Of the 48 evaluable pts, 64.6% (31/48) were previously treated with an anti-EGFR agent. No new adverse events (AEs) were observed and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Among 48 pts enrolled who received RECIST evaluation, Disease Control Rate (DCR) was observed in 25 pts (52.1%) of which 3 pts achieved PR (6%) and 22 pts achieved SD (45%). Among 31 pts previously treated with anti-EGFR therapy, DCR was observed in 15 pts (48%) compared with DCR of 59% observed in 10 out of 17 anti-EGFR naïve pts receiving a scan. Conclusions: This phase II study confirmed that napabucasin can be safely combined with panitumumab at full dose and shows encouraging anti-tumor activity in pts with K- Ras wt mCRC, regardless of prior anti-EGFR exposure, suggesting that napabucasin may sensitize pts to repeat anti-EGFR therapy. Clinical trial information: NCT01776307. [Table: see text]

scholarly journals Opposite Effects of Single-Dose and Multidose Administration of the Ethanol Extract of Danshen on CYP3A in Healthy Volunteers

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Furong Qiu ◽  
Jian Jiang ◽  
Yueming Ma ◽  
Guangji Wang ◽  
Chenglu Gao ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
In Vitro Study ◽  
Ethanol Extract ◽  
Tanshinone Iia ◽  
Open Label ◽  
The Mean

The aim of this study was to investigate the effect of single- and multidose administration of the ethanol extract of danshen on in vivo CYP3A activity in healthy volunteers. A sequential, open-label, and three-period pharmacokinetic interaction study design was used based on 12 healthy male individuals. The plasma concentrations of midazolam and its metabolite 1-hydroxymidazolam were measured. Treatment with single dose of the extract caused the meanCmaxof midazolam to increase by 87% compared with control. After 10 days of the danshen extract intake, the mean AUC0–12,Cmax, andt1/2of midazolam were decreased by 79.9%, 66.6%, and 43.8%, respectively. The mean clearance of midazolam was increased by 501.6% compared with control. The in vitro study showed that dihydrotanshinone I in the extract could inhibit CYP3A, while tanshinone IIA and cryptotanshinone could induce CYP3A. In conclusion, a single-dose administration of the danshen extract can inhibit intestinal CYP3A, but multidose administration can induce intestinal and hepatic CYP3A.

A Humanized Anti-Ganglioside GM2 Antibody, BIW-8962, Exhibits ADCC/CDC Activity against Multiple Myeloma Cells and Potent Anti- Tumor Activity in Mouse Xenograft Models.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1718-1718 ◽  
Author(s):  
Toshihiko Ishii ◽  
Asher Alban Chanan-Khan ◽  
Jazur Jafferjee ◽  
Noreen Ersing ◽  
Takeshi Takahashi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Phase 1 ◽  
Xenograft Model ◽  
Surface Expression ◽  
Scid Mice ◽  
Subcutaneous Xenograft ◽  
Anti Tumor Activity

Abstract BIW-8962 is a humanized anti-ganglioside GM2 (GM2) monoclonal antibody, produced by Poteligent technology to enhance ADCC activity. GM2 is expressed on many cancer cells including multiple myeloma (MM), small cell lung cancer and glioma cells. In this study, we evaluated the anti-myeloma activity of BIW-8962 in preclinical myeloma models both in vitro and in vivo. Expression of GM2 was analyzed in 15 human MM cell lines by FCM. Eleven out of 15 MM cell lines had positive surface expression of GM2. GM2 as a potential target was then verified in primary MM samples obtained from patients. Eleven out of 15 samples were positive for GM2. We then used two GM2 positive MM cell lines (U266B1 and KMS-11) and evaluated ADCC and CDC activity of BIW-8962 in vitro. BIW-8962 exhibited a potent ADCC and less potent CDC activity. In vivo anti-tumor activity of BIW-8962 was then examined using the standard subcutaneous xenograft model; KMS-11 was inoculated in the flank of SCID mice. BIW-8962 (intravenously administered biweekly for 3 weeks) exhibited a potent anti-tumor activity from as low a dose level as 0.1 mg/kg. Furthermore, in a more clinically relevant model, in which OPM-2/GFP (GM2 positive MM cell line) cells were intravenously inoculated into SCID mice with preferentially tumor growth within the bone marrow microenvironment, BIW-8962 (intravenously administered biweekly for 4 weeks, 10 mg/kg) suppressed OPM-2/GFP cell growth and serum M protein elevation, demonstrating in vivo anti-myeloma effect of BIW-8962. Our preclinical investigations rationalize clinical evaluation of BIW-8962 in patients with MM. Currently BIW-8962 is being investigated in a Phase 1 study in patients with multiple myeloma.

Prevention of base excision repair by TRC102 (methoxyamine) potentiates the anti-tumor activity of pemetrexed in vitro and in vivo

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13005-13005 ◽  
Author(s):  
L. Liu ◽  
A. Bulgar ◽  
J. Donze ◽  
B. J. Adams ◽  
C. P. Theuer ◽  
...  
Keyword(s):  
Excision Repair ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Ap Sites ◽  
Dna Strand ◽  
Anti Tumor Activity

13005 Background: TRC102 (methoxyamine) reverses resistance to alkylating agents by inhibiting base excision repair (BER; a mechanism of DNA repair), thereby increasing DNA strand breaks and potentiating the anti-tumor activity of alkylating agents without additional toxicity, Based on these data, TRC102 is currently being studied in combination with temozolomide in a phase 1 trial. We hypothesized that inhibition of BER by TRC102 would also increase DNA strand breaks and improve the anti-tumor activity of anti-metabolite chemotherapeutics, including pemetrexed, because these agents also produce AP sites that are recognized and repaired by BER. Methods: Pemetrexed- induced AP sites and BER inhibition was quantified using an apurinic/apyrimidinic (AP) site assay in vitro. Single and double DNA strand breaks were quantified by the Comet assay in vitro and anti-tumor activity was assessed in an in vivo xenograft study of subcutaneously implanted H460 human lung cancer cells. Results: Pemetrexed induced and TRC102 reduced the number of available AP sites in pemetrexed- treated H460 cells (by 60–80%), indicating successful inhibition of BER. TRC102 treatment increased DNA strand breaks in pemetrexed-treated H460 cells (2 fold increase versus treatment with pemetrexed alone). Premetrexed treatment alone and in combination with TRC 102 delayed tumor growth in vivo (tumor growth delay of 4.7 days in the 150 mg/m2 pemetrexed alone group, 5.7 days in the 150 mg/m2 pemetrexed + 2 mg/m2 TRC102 group and 6.9 days in the 150 mg/m2 pemetrexed + 4 mg/m2 TRC102 group); in vivo systemic toxicity was not increased. TRC102 alone had no effect in vitro or in vivo. Conclusions: TRC102 effectively inhibits BER in lung cancer cells treated with pemetrexed. Inhibition of DNA repair by TRC102 results in an increase in DNA strand breaks and improved anti-tumor activity versus treatment with pemetrexed alone. Given its preclinical efficacy and safety profile, study of TRC102 combined with pemetrexed in a phase 1 trial is warranted. No significant financial relationships to disclose.

Phase I dose-escalation study of pasireotide LAR in patients with advanced neuroendocrine tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15126-e15126 ◽  
Author(s):  
Alexandria T. Phan ◽  
Edward M. Wolin ◽  
Jennifer A. Chan ◽  
Jerry M. Huang ◽  
Michelle Hudson ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Somatostatin Receptor ◽  
Plasma Concentrations ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Best Response ◽  
Long Acting

e15126 Background: Somastatin analogs (SSA), including octreotide and lanreotide, bind predominantly to somatostatin receptor (SSTR) 2 and form the foundation of treatment for symptomatic neuroendocrine tumors (NET). Pasireotide, a novel SSA with a broad binding affinity (SSTR 1-3 and 5), is being explored for treatment of NET. A phase 1 dose-escalation study (NCT01364415) of pasireotide long-acting release (LAR; starting dose of 80 mg) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and to characterize safety, tolerability, pharmacokinetics, and efficacy in pts with advanced NET. Methods: Pts with advanced, well- or moderately differentiated NET received pasireotide LAR beginning at a dose of 80 mg q28d. Successive cohorts will receive doses (up to 220 mg) guided by a Bayesian logistic regression model until MTD/RP2D is reached. Results: To date, 15 pts have been treated at 80 mg (n=6) and 120 mg (n=9). Median age is 59 (44-76) years. Primary tumor sites include small intestine (40%), pancreas (20%), and lung (13.3%). All pts received prior antineoplastic therapy; 93% received prior SSA. Median number of cycles of pasireotide was 6.68 (2-14) (1 cycle=28 days). 10 (67%) pts remain on treatment: 3 on 80 mg and 7 on 120 mg. 5 (33%) have discontinued (disease progression, 2 pts; withdrew consent, 2 pts; adverse event [AE], 1 pt). Median plasma concentrations of pasireotide increased with dose. No dose-limiting toxicities have been reported. Most frequent AEs were similar in both dose groups and included hyperglycemia (87%), diarrhea (53%), abdominal pain (47%), nausea (40%), anemia (33%), and fatigue (33%). Most AEs were mild/moderate. 2 pts (1 in each group) had grade 3 hyperglycemia. 4 (27%) and 2 (13%) pts had HbA1C increase from <6.5% at baseline to 6.5-<8% and ≥8%, respectively. 13 (87%) pts had radiographically stable disease as best response. More pts at 120 mg (50%) vs 80 mg (33%) achieved ≥50% reduction in chromogranin A. Conclusions: Pasireotide LAR up to 120 mg appears to be well tolerated in patients with advanced NET. The study is ongoing. Pasireotide represents a promising therapy for pts with NET. Clinical trial information: NCT01364415.

Phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 administered in combination with FOLFIRI with and without bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 569-569 ◽  
Author(s):  
Joleen Marie Hubbard ◽  
Bert H. O'Neil ◽  
Derek J. Jonker ◽  
Thorvardur Ragnar Halfdanarson ◽  
Alexander Starodub ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tumor Regression ◽  
Progression Free Survival ◽  
Open Label ◽  
Cancer Stemness ◽  
Phase Ib ◽  
Heavily Pretreated ◽  
Anti Tumor Activity

569 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo,in mono and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was undertaken to confirm the RP2D of BBI-608 in combination with FOLFIRI with or without BEV. BBI-608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2infusion) with or without BEV 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 18 heavily pretreated pts with an average of > 3 prior lines of therapy of which 10 pts (56%) previously progressed on FOLFIRI were enrolled. Of the 17 pts evaluable for response, 8 pts received FOLFIRI and 9 pts received FOLFIRI with BEV in combination with BBI-608. Most common adverse events included grade 1 and 2 diarrhea, abdominal pain, nausea, vomiting and anorexia. No dose limiting toxicity or new adverse events were seen, and the safety profile was similar to that of each regimen as monotherapy. Grade 3 events related to protocol therapy included diarrhea occurring in 3 pts, fatigue in 2 pts and dehydration in 1 pt. All events resolved after dose reduction and/or start of anti-diarrheal medications. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 16 of 17 evaluable pts (94%) with 2 PR (per RECIST 1.1 criteria: 44% and 33% regression) and 14 SD (of which 13 (93%) had tumor regression < 25%). In the evaluable pts, median progression free survival was 5.54 months. Of 17 pts, 7 (41%) had prolonged SD of > 6 months. Conclusions: This phase Ib study confirmed that BBI-608 at 240 mg bid can be safely combined with FOLFIRI with and without BEV, and shows encouraging anti-tumor activity in heavily pretreated CRC pts, even in pts with prior progression on FOLFIRI-based therapy. Clinical trial information: NCT02024607.

BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13525-e13525 ◽  
Author(s):  
Warren P. Mason ◽  
Paula de Robles ◽  
Laura Borodyansky ◽  
Matthew Hitron ◽  
Waldo Feliu Ortuzar ◽  
...  
Keyword(s):  
Recurrent Glioblastoma ◽  
Open Label ◽  
Cancer Stemness ◽  
Phase Ib ◽  
Anti Cancer ◽  
First Recurrence ◽  
Multi Center Study ◽  
Anti Tumor Activity

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]

scholarly journals Induction of Fetal Hemoglobin By FTX6058, a Novel Small Molecule Development Candidate

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Peter Rahl ◽  
Ivan Efremov ◽  
Billy Stuart ◽  
Keqiang Xie ◽  
Mark Roth ◽  
...  
Keyword(s):  
Small Molecule ◽  
Plasma Concentrations ◽  
Fetal Hemoglobin ◽  
Target Engagement ◽  
Publicly Traded ◽  
In Vivo Models ◽  
Α Subunit ◽  
The Past

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Two phase 1 studies of MPC-6827, a novel vascular disrupting agent (VDA), in patients with advanced solid tumors and CNS metastases

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3604-3604 ◽  
Author(s):  
R. Kurzrock ◽  
W. Akerley ◽  
D. Hong ◽  
C. Ng ◽  
T. Warren ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Neurological Deficits ◽  
Two Phase ◽  
Vascular Disrupting Agent ◽  
Coronary Syndrome

3604 Background: MPC-6827 is a novel competitive inhibitor of tubulin polymerization via the colchicine binding site and functions as a highly potent (1–10nM) cytotoxic agent and as a VDA. MPC-6827 inhibits tumor cell growth and survival in vitro and in vivo, with activity in xenograft models of mouse melanoma and human cancers of the ovary, breast, prostate, colon and pancreas. The compound is not a substrate for multidrug resistance pumps and reaches high CSF concentrations. Methods: Two 3+3 designed dose-escalating Phase 1 studies were conducted to define the safety, tolerability, maximum tolerated dose (MTD) and PK of weekly IV administrations of MPC-6827 for pts with advanced solid malignancies (trial 1; N=46 pts) and measurable CNS involvement (trial 2; N=17 pts). In trial 2, there was intrasubject dose escalation for the first cycle and subsequent cycles were dosed at the highest dose achieved in Cycle 1. Antitumor activity was evaluated by RECIST guidelines in both studies. Results: Dose escalation proceeded until MTD was determined at 3.3 mg/m2. The dose limiting toxicity was acute coronary syndrome. Common mild to moderate toxicities included fatigue, headache, flushing, diarrhea, nausea, vomiting and arthralgias. There were no neurological deficits observed and no evidence of myelosuppression. No objective responses were observed. Radiographic changes consistent with vascular disruption in tumors were documented in a number of subjects at higher doses. Conclusions: MPC-6827 is safe and overall well tolerated. MTD is 3.3 mg/m2. Vascular flow modulation analyses are ongoing. MPC-6827 is currently in Phase 2 development. No significant financial relationships to disclose.

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