CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi64
Author(s):  
Zhong-ping Chen ◽  
Cheng-Cheng Guo ◽  
Yang Qun-ying ◽  
Jia-Wei Li ◽  
Shao-xiong Wu ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Radiation Treatment ◽  
Gene Promoter ◽  
Progression Free Survival ◽  
Common Adverse Event ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

scholarly journals SYST-05. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv9-iv9
Author(s):  
Zhong-ping Chen ◽  
Cheng-cheng Guo ◽  
Qun-ying Yang ◽  
Jia-wei Li ◽  
Shao-xiong Wu ◽  
...  
Keyword(s):  
Radiation Treatment ◽  
Progression Free Survival ◽  
Median Number ◽  
Common Adverse Event ◽  
In Vivo Studies ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study

Abstract VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemo-resistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.

scholarly journals CTNI-76. PHASE 2 CLINICAL TRIAL OF VAL-083 IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii60-ii60
Author(s):  
Zhong-ping Chen ◽  
Cheng-Cheng Guo ◽  
Qun-ying Yang ◽  
Shao-xiong Wu ◽  
Jia-Wei Li ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Dna Methyltransferase ◽  
Radiation Treatment ◽  
Common Adverse Event ◽  
Initial Assessment ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Mgmt Promoter

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) promoter region, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation safety and tolerability phase to confirm the phase 2 dose of VAL-083 when administered concurrently with radiation therapy (RT). Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week). The dose escalation stage is complete, and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 comprises an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. As of June 2, 2020, all patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. Of the 29 patients enrolled, 27 have completed their prospectively planned MRI scans and had their initial assessment for tumor response. Two additional patients died prior to their post-cycle 3 MRI. Consistent with our prior experience, myelosuppression was the most common adverse event. Three patients have experienced dose-limiting toxicities - one (1/3; 33%) at the 40 mg/m2/day and two (2/25; 8%) at the 30 mg/m2/day dose. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

scholarly journals ACTR-12. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi14-vi15
Author(s):  
Barbara O’Brien ◽  
Marta Penas-Prado ◽  
Carolos Kamiya ◽  
Shiao- Pei Weathers ◽  
Alfred Yung ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Safety Data ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Common Adverse Event ◽  
Hematological Toxicity ◽  
Phase 2 ◽  
Current Standard ◽  
Phase 2 Study ◽  
Recurrent Gbm

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1–5 every 28 days. Almost all GBM patients experience recurrent/progressive disease, with a median survival after recurrence of 3–9 months. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine, induces double-strand breaks and acts independent of MGMT DNA repair. The current ongoing trial is a biomarker-driven Phase 2 study in MGMT-unmethylated BEV-naïve adult GBM. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) for MGMT-unmethylated GBM patients compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life. Thirty-five (35) subjects with recurrent GBM have received 40 mg/m2/day VAL-083 on days 1, 2, 3 of a 21-day cycle as the starting dose. Myelosuppression is the most common adverse event and a higher potential for this toxicity correlated with those patients who received a higher number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ≤5 cycles, p< 0.05). To minimize the potential for hematological toxicity in rGBM, subsequent subjects initiated treatment at 30 mg/m2/d VAL-083 x 3 consecutive days every 21 days. In addition, since TMZ is of limited value in the MGMT-unmethylated setting, a second arm in newly diagnosed GBM has been included to explore whether substituting TMZ with VAL-083 offers clinical benefit and extends the time to recurrence. Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

scholarly journals Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease

Blood ◽  
2019 ◽  
Vol 133 (16) ◽  
pp. 1720-1728 ◽  
Author(s):  
Lu Zhang ◽  
Ai-lin Zhao ◽  
Ming-hui Duan ◽  
Zhi-yuan Li ◽  
Xin-xin Cao ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Progression Free Survival ◽  
Castleman Disease ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Multicentric Castleman Disease ◽  
End Point ◽  
Phase 2 Study ◽  
Grade 3

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti–interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P &lt; .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

scholarly journals Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2352-2366 ◽  
Author(s):  
Guo-zhong Yi ◽  
Guanglong Huang ◽  
Manlan Guo ◽  
Xi’an Zhang ◽  
Hai Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Dna Lesions ◽  
Dna Repair Proteins

Abstract The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

Phase 2 study of pembrolizumab in combination with azacitidine in subjects with metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
James J. Lee ◽  
Weijing Sun ◽  
Nathan Bahary ◽  
James Ohr ◽  
John C. Rhee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Metastatic Colorectal Cancer ◽  
Tumor Progression ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Anti Tumor Activity ◽  
Study Therapy

3054 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has relatively poor tumoral infiltration of CD8+ T cells and is resistant to pembrolizumab (Pembro) when compared to MSI-H mCRC. DNA hypomethylating agent induces epigenetic expression of multiple genes including cancer-testis antigens in CRC, which are recognized by cytotoxic CD8+ T cells in vitro and in vivo. This trial tested whether concurrent treatment with azacitidine (Aza) could enhance the anti-tumor activity of Pembro. Methods: This is a phase 2 trial to evaluate anti-tumor activity and safety of Pembro plus Aza in patients (pts) with previously treated mCRC without any further standard chemotherapy option. Pts received Pembro 200 mg IV on day 1 of each cycle Q3W and Aza 100 mg daily SQ injection on days 1-5 of each cycle Q3W. Primary endpoint was response rate (ORR) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Tumor tissues were collected for correlative studies. Results: Thirty-one pts were enrolled [median age, 61 years (range, 30-79); 17 M/14 F; ECOG PS 0/1 (58%/42%); 30 pts with MSS mCRC]. Pts received at least 2 lines of prior systemic chemotherapy for mCRC (median, 3; range, 1-5). Thirty pts received at least one dose of study therapy (median, 3 cycles; range, 1-8). Ten pts could not complete the first 3 cycles due to rapid symptomatic tumor progression. One pt with MSS mCRC achieved PR and 3 pts had SD as best response. The ORR was 3% (1/30; 95% CI, 0.1-17%). Seven pts with PD at the end of cycle 3 continued on study therapy, and 2 pts had stabilization of tumor progression. Median PFS was 2.1 months (95% CI, 1.8-2.8), and median OS was 6.2 months (95% CI, 3.5-8.7). While treatment-related adverse events (TRAEs) were reported in 63% of pts, most of the TRAEs were Gr 1/2 (96%). Frequent TRAEs possibly related to Aza were anemia (n = 5), constipation (n = 5), and leukopenia (n = 4); and possibly related to both Aza and Pembro were nausea (n = 5) and fatigue (n = 5). Gr 3 TRAEs included anemia (n = 1), ALT elevation (n = 1), and alkaline phosphatase elevation (n = 1). Conclusions: Pembro plus Aza is feasible with a tolerable safety profile but appears to have minimal anti-tumor effect for MSS mCRC. Clinical trial information: NCT02260440.

scholarly journals Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma

2010 ◽  
Vol 28 (16) ◽  
pp. 2712-2718 ◽  
Author(s):  
Roger Stupp ◽  
Monika E. Hegi ◽  
Bart Neyns ◽  
Roland Goldbrunner ◽  
Uwe Schlegel ◽  
...  
Keyword(s):  
Phase I ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Purpose Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods Patients (age ≥ 18 to ≤ 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.

Clinical trials of VAL-083 in patients with chemo-resistant glioblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2082-TPS2082
Author(s):  
Jeffrey A. Bacha ◽  
Anne Steino ◽  
Richard Stephen Schwartz ◽  
John Langlands ◽  
Sarath Kanekal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Dna Methyltransferase ◽  
Drug Application ◽  
Phase 2 ◽  
Current Standard ◽  
Pivotal Phase ◽  
Phase 2 Study ◽  
Recurrent Gbm

TPS2082 Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand DNA cross-links, double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells, independent of MGMT status in vitro. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested that VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointed a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle) which was well-tolerated and was selected for study in subsequent GBM trials. Methods: These trials include i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival at 9 months, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab. The control arm will consist of a limited number of salvage chemotherapies currently used in bevacizumab-failed GBM. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Clinical trial information: NCT02717962.

Randomized phase II study of IV topotecan versus CRLX101 in the second-line treatment of recurrent extensive-stage small cell lung cancer (ES-SCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS7610-TPS7610
Author(s):  
Thomas A. Hensing ◽  
Theodore Karrison ◽  
Edward Graeme Garmey ◽  
Meliessa G. Hennessy ◽  
Ravi Salgia
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Objective Response ◽  
Systemic Exposure ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Phase 2 ◽  
Polymer Conjugate

TPS7610 Background: SCLC remains an area of high unmet medical need with an aggressive clinical course and < 10% 5-year overall survival. In the U.S., topotecan (Hycamtin, GlaxoSmithKline) is the reference standard for treatment of chemotherapy (C)-sensitive (S) relapsed disease but its use remains compromised by toxicity. There currently exists no standard therapy for patients (pts) with C-resistant (R) disease (relapse occurring < 60 days from last C). CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles and delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 compared to approved agents in multiple animal tumor models including SCLC. A monotherapy recommended phase 2 dose of 15 mg/m2 IV every 2 weeks has now been administered to over 150 cancer pts across five ongoing phase 2 clinical trials. Methods: This ongoing, randomized phase 2 clinical trial compares the effect on progression free survival (PFS) of 2nd-line treatment with IV CRLX101 (15 mg/m2 on days 1 and 15 every 28 days) to IV topotecan (1.5 mg/m2 on days 1-5 every 21 days) in pts with CS relapsed ES-SCLC. In parallel, the effect of 2nd-line CRLX101 on 3-mo. PFS rate of pts with CR relapsed ES-SCLC will be evaluated. Secondary objectives in both cohorts include evaluation of objective response rates (by RECIST v1.1), overall survival, and safety. In the randomized cohort, 112 pts (56/arm) will be enrolled in order to achieve 90% power to detect an improvement in median PFS from 3 to 5 mos. (HR=0.60). An interim analysis will be performed after 1/2 of expected PFS events have occurred. Pts with CR disease will all receive CRLX101 and the trial will employ a 2-stage design: 14 pts will be enrolled in stage 1 and the study will be terminated if ≤ 3 pts remain progression free at 3 mos. Otherwise, an additional 30 pts will be enrolled and if ³ 15/44 (34%) pts remain progression free at 3 mos., the drug will be considered worthy of further investigation. The first patient on this clinical trial was enrolled on January 30, 2013. Clinical trial information: NCT# is pending.

004 Samelisant (SUVN-G3031), Differentiating features over current treatments of narcolepsy

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A2-A2
Author(s):  
Anil Shinde ◽  
Ramkumar Subramanian ◽  
Raghava Palacharla ◽  
Vijay Benade ◽  
Renny Abraham ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Abuse Liability ◽  
Species Variation ◽  
Phase 2 ◽  
Pharmacological Agents ◽  
Inverse Agonists ◽  
Phase 2 Study ◽  
Sigma 1

Abstract Introduction Majority of pharmacological agents used in the treatment of narcolepsy have several limitations. Both nonclinical and clinical evidences suggest usefulness of the histamine H3 receptor (H3R) inverse agonists for the treatment of narcolepsy addressing several of the current limitations. Methods Extensive nonclinical studies were carried out for Samelisant (SUVN-G3031) and other pharmacological agents that are currently being used for the treatment of narcolepsy. The nonclinical parameters like inter-species binding affinity, selectivity profile, in vivo and in vitro ADME features, nonclinical efficacy, neurochemistry and safety were compared. Results Samelisant has no inter-species variation in binding affinity at H3R with less than 50% inhibition at 1 µM against 70 other targets. Unlike pitolisant, Samelisant has no significant binding affinity at sigma 1 and 2 receptor. Samelisant has no inhibition and induction liability towards major CYP enzymes and transporters. Pitolisant is reported to be a CYP3A4, CYP2B6, and CYP1A2 inducer and a CYP2D6 and OCT1 inhibitor. Samelisant has robust wake promoting effects. Samelisant showed negligible affinity towards hERG channel with IC50 &gt; 10 µM and had no effects on heart rate or ECG parameters in dog telemetry study. Samelisant did not show convulsion in rats up to the tested dose of 100 mg/kg, p.o. Most of the pharmacological agents used for the treatment of narcolepsy have abuse liability; Samelisant produced no change in the striatal and accumbal dopamine levels in rats suggesting no propensity to induce abuse liability. Unlike competing H3R inverse agonists, Samelisant has no effects on fertility and embryo-fetal development up to the highest tested doses. Conclusion Nonclinical studies demonstrated superiority of Samelisant over pharmacological agents used in the treatment of narcolepsy. Samelisant is currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Support (if any):

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