scholarly journals DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii297-iii297
Author(s):  
Sharon Gardner ◽  
Rohinton Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
Yazmin Odia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Phase I ◽  
Single Agent ◽  
High Grade Glioma ◽  
Newly Diagnosed ◽  
Liquid Formulation ◽  
Open Label ◽  
Dismal Prognosis ◽  
Expansion Cohort

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPG.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3619-3619
Author(s):  
Sharon L. Gardner ◽  
Carl Johannes Koschmann ◽  
Rohinton Tarapore ◽  
Jeffrey C. Allen ◽  
Wafik Tharwat Zaky ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Single Agent ◽  
High Grade Glioma ◽  
Biologically Active ◽  
High Grade ◽  
Newly Diagnosed ◽  
Preclinical Models ◽  
Open Label ◽  
The Impact

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 .

ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10046-10046 ◽  
Author(s):  
Sharon L. Gardner ◽  
Jeffrey C. Allen ◽  
Wafik Tharwat Zaky ◽  
Yazmin Odia ◽  
Doured Daghistani ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Dose Escalation ◽  
Single Agent ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Open Label ◽  
Body Weights ◽  
Label Dose

10046 Background: ONC201 is the first DRD2 antagonist for clinical oncology. The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients. 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 multicenter, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) determined the RP2D of ONC201 in pediatric H3 K27M-mutant glioma patients as a single agent. ONC201 was orally administered once a week and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with one 125mg capsule less than the adult RP2D equivalent. Three patients were treated at the starting dose and 19 were treated at the adult RP2D equivalent. Results: The primary endpoint was achieved by establishing the safety of the adult RP2D scaled by body weight to pediatric patients. Twenty-two patients with a median age of 9 (range 3-18) years old who received at least prior radiation have been treated with ONC201: 15 with diffuse intrinsic pontine glioma (DIPG) (4 recurrent; 11 not recurrent) and 7 with non-DIPG H3 K27M-mutant glioma (all not recurrent). As of February 5, 2019, patients have received a median of 18 ONC201 doses (range 3-41) without instance of dose-limiting toxicity. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL) and exposure was similar across body weights. Nine of 22 patients remain on therapy, 13 have discontinued due to progression, and 4 off-study patients are alive with a median follow up of 5.8 months. Five of the 11 (45%) DIPG patients who initiated ONC201 following radiation, but prior to recurrence, remain on therapy (median 7.4 months; range 4.4-9.6): median PFS is 4.4 months from initiation of ONC201 and 9.7 months from diagnosis; 7 of 11 (64%) patients are alive with median follow up of 11.8 months from diagnosis. Conclusions: ONC201 was well tolerated and achieved therapeutic exposure in pediatric H3 K27M-mutant glioma patients at the adult RP2D scaled by body weight. Further investigation of first-line ONC201 to treat H3 K27M-mutant glioma and/or DIPG is ongoing. Clinical trial information: NCT03416530.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals CTNI-15. CLINICAL EFFICACY OF ONC201 IN NEWLY DIAGNOSED DIPG AND IN PREVIOUSLY IRRADIATED PEDIATRIC H3 K27M-MUTANT GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii45-ii45
Author(s):  
Sharon Gardner ◽  
Carl Koschmann ◽  
Rohinton S Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
...  
Keyword(s):  
Body Weight ◽  
Single Agent ◽  
Biologically Active ◽  
Pharmacokinetic Analysis ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Liquid Formulation ◽  
Phase Ii Trials ◽  
Body Weights ◽  
Post Radiation

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.

A phase I/II study combining tosedostat with capecitabine in patients with metastatic pancreatic adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS471-TPS471
Author(s):  
Andrea S. Teague ◽  
Manik A. Amin ◽  
Kian-Huat Lim ◽  
Albert C. Lockhart ◽  
Ashiq Masood ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Phase I ◽  
Phase Ii ◽  
Primary Objective ◽  
Cellular Stress Response ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Pancreatic Cancer Cells ◽  
Dismal Prognosis

TPS471 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Recent advances with fluorouracil in combination with oxaliplatin and irinotecan (FOLFIRINOX) and nab-paclitaxel combined with gemcitabine (AG) have improved survival in patients with PDAC. A fluorouracil-based regimen is recommended for patients who progress after a gemcitabine-based regimen. Tosedostat is an oral aminopeptidase inhibitor shown to have anti-proliferative effects in malignancies. Aminopeptidase inhibitors disrupt the cleavage of amino acids from peptides downstream of proteasomal degradation, preventing the recycling of amino acids needed for new protein synthesis. This leads to intracellular depletion of amino acids, resulting in a cellular stress response known as the amino acid deprivation response, which leads to apoptosis. Because pancreatic cancer cells frequently upregulate expression of these aminopeptidases, aminopeptidases inhibitors hold therapeutic promise. Methods: This is a single institution phase I/II open-label trial to evaluate the safety and tolerability of tosedostat plus capecitabine in patients with metastatic PDAC that have progressed after a gemcitabine-based regimen. The phase I part will be conducted in a dose de-escalation fashion, with two planned dose levels of tosedostat (120mg or 60mg) p.o. daily on days 1 to 21 with capecitabine 1000 mg/m2 p.o. BID on days 1 to 14 of a 21-day cycle. If more than one patient in the tosedostat (120 mg) cohort experiences a dose limiting toxicity (DLT), then 6 more patient will be enrolled to the tosedostat (60 mg) cohort. A total of 36 patients will be enrolled in the phase II portion. Primary objective of the phase I portion is to determine the maximum tolerated dose and DLTs of tosedostat and capecitabine combination therapy. Primary objective of the phase II portion is to determine the progression-free survival at 3 months. Secondary objectives are to determine the overall response rate, time-to-progression, overall survival and CA 19-9 response. Exploratory objectives are to explore the predictive molecular biomarkers for treatment response and to explore the prognostic biomarkers. Clinical trial: NCT02352831. Clinical trial information: NCT02352831.

Pharmacodynamic evaluation of pCDC2 as the target engagement biomarker to assess activity of MK-1775 a Wee1 tyrosine kinase inhibitor.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13598-e13598
Author(s):  
Shelonitda Rose ◽  
Jonathan D. Cheng ◽  
Johnny Viscusi ◽  
Robert Iannone ◽  
Jan HM Schellens ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Locally Advanced ◽  
Target Engagement ◽  
Open Label ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Skin Biopsies

e13598 Background: Wee1 kinase regulates the G2 checkpoint through phosphorylation of CDC2. MK-1775 is a first-in-class inhibitor of Wee1, and thereby reduces pCDC2 levels relative to CDC2. pCDC2therefore can be used as a target engagement (TE) biomarker to assess activity of MK-1775. This was investigated in a phase I first-in-man clinical trial of MK-1775. Methods: This is a multicenter, open-label, non-randomized phase I dose escalation study in patients with locally advanced or metastatic solid tumors. MK-1775 was administered orally in escalating doses as monotherapy, and either single dose or multi-dose in combination with chemotherapy including cisplatin, carboplatin and gemcitabine. Serial skin biopsies were performed at baseline and either 8, 24 or 48 hours following MK-1775 administration and analyzed by IHC for CDC2 and pCDC2. Based on preclinical efficacy experiments, TE was defined as a decrease of pCDC2 of at least 50% (or fold change > 0.50) from pre- to post-dose MK-1775. Results: To date a total of 176 patients have received at least one dose of MK-1775 either as monotherapy or in combination (single or multi-dose MK-1775) with chemotherapy at doses ranging from 25 mg to 1300 mg to define maximum tolerated dose. Dose dependent decreases in pCDC2 were observed in skin biopsies between pre-dose and post-dose treatment in all treatment groups. TE with monotherapy was achieved at 325 mg. TE with multi-dose MK-1775 in combination with cisplatin and carboplatin were achieved at 125 mg BID and 225 mg BID. Gemcitabinecombination treatment is on-going. In contrast, chemotherapy alone resulted in an increase of pCDC2. Conclusions: Based on preclinical data, in this first-in-man clinical trial of MK-1775, we were able to demonstrate TE required for maximal efficacy at tolerable doses of MK-1775 either as a single agent or in combination with chemotherapy. [Table: see text]

scholarly journals OS5.1 Phase I clinical trial with oncolytic virus DNX-2401 for DIPGs

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii11-iii11
Author(s):  
M M Alonso ◽  
I Iñigo ◽  
M Gonzalez-Huarriz ◽  
P Dominguez ◽  
A Patiño ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Phase I ◽  
Brain Mri ◽  
Combined Treatment ◽  
High Grade Glioma ◽  
Phase I Clinical Trial ◽  
Close Monitoring ◽  
Newly Diagnosed ◽  
Tumor Biopsy

Abstract BACKGROUND Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. Recently our group has showed that the virus is safe and effective in preclinical models of pHGG and DIPG. Moreover, we showed that the virus is able to trigger an antitumor immune response. These outstanding preclinical results allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. MATERIALS AND METHODS A phase I clinical trial with DNX-2401 for patients with newly diagnosed DIPG to assess the MTD is taking place in our hospital (N=12). Tumor biopsy is performed through the cerebellar peduncle, followed by virus injection. The virus is injected using a cannula, MEMS cannula (Alcyone Lifesciences) that prevents the reflux. Virus will be injected starting with 1010 pv. The trial is uncontrolled, unicentric with a 3 + 3 design. The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in subjects with DIPG and to collect tumor samples of this type of tumor. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. The follow up includes close monitoring of neurological status, blood tests and brain MRI. If this trial shows evidence of safety and efficacy will propel a multicenter clinical trial. RESULTS All the clinical data from the trial available until September 2019 will be presented during the congress, to date 8 patients have been treated within the trial. Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. Patients were home 3–4 days after the injection. All the patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 6 out of the 8 patients. We are currently assessing the immune responses to the virus. CONCLUSIONS Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies and therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumors.

Interim Results of a Phase I/II Clinical Trial of Belinostat in Combination with Idarubicin in Patients with AML Not Suitable for Standard Intensive Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1953-1953 ◽  
Author(s):  
Richard Schlenk ◽  
Kristina Sohlbach ◽  
Marie-Luise Hütter ◽  
Patrice Ceballos ◽  
Nathalie Fegueux ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
De Novo ◽  
Intensive Therapy ◽  
Single Agent ◽  
Prior Treatment ◽  
Pharmacokinetic Analysis ◽  
Open Label ◽  
Dismal Prognosis ◽  
Dose Limiting Toxicity

Abstract Patients either with refractory/relapsed AML or with newly diagnosed AML not suitable for intensive induction therapy have a dismal prognosis. Belinostat belongs to a new class of hydroxymate-type histone deacetylase (HDAC) inhibitors. Belinostat has demonstrated effective cell killing in leukemic and lymphoma cells as a single agent and synergy in combination with other therapeutic regimens such as anthracyclines. Preliminary results are presented of the still ongoing open-label non-randomized, multi-centre, phase I/II trial to assess the efficacy and safety of 2 schedules of belinostat in combination with idarubicin in patients with AML not suitable for standard intensive therapy. Belinostat was administered either as a daily 30 min infusion for 5 days q 3 weeks plus iv idarubicin on days 4+5 (regimen A) or as a continuous iv administration over 48 hours q 2 weeks with addition of iv idarubicin at h 24 and 48 (regimen B). Both schedules used a dose escalation design; regimen A, the 3+3 dose escalation design; regimen B, the accelerated titration design. Currently, 22 patients have been treated (regimen A, n=11; regimen B, n=11). Patient characteristics at inclusion were as follows: median age 72 years (range 37–84); 12 had de novo AML, all were in relapse from previous treatment, 4 had secondary AML, two had received prior treatment, 7 had MDS/AML, 3 received prior treatment. In total, 49 cycles of trial treatment were administered in 22 patients (median = 2, range 1 – 8). The safety database as of 11.07. 2008 with information available for 19 patients (n=10 in regimen A. n=9 in regimen B) only contained two SAE’s defined by the investigators as related to treatment, they occurred in the same patient and were of the same type neutropenia and thrombocytopenia, conditions known as associated with idarubicin and also fundamentally a part of the progressive leukemic process and therefore in part exempted from the DLT definition in this as in other AML treatment protocols. So far no dose limiting toxicity was defined. Most frequent related adverse events, occurring in less than one third of the patients, were nausea, vomiting, diarrhea. Antileukemic efficacy was seen both following belinostat single agent (CRi after 2 cycles in one 62 yr old MDS/AML patient receiving 48h CIV at a dose of 800 mg/m2/d, regimen B) and following belinostat in combination with idarubicin (CRi after one cycle in one 84 yr old MDS/AML patient receiving 48h CIV at a dose of 1000 mg/m2/d plus idarubicin 5 mg/m2 x1, regimen B; CR after one cycle in one 74 yr old AML patient receiving the 5-d regimen of belinostat 1000 mg/m2/d + idarubicin 10 mg/m2 x 1 and extramedullary cutaneous relapse after the 8th cycle, regimen A; CRi after 3 cycles in one 78 yr old MDS/AML patient receiving the 5-d regimen of belinostat 1000 mg/m2/d + idarubicin 7.5 mg/m2 x 2, regimen A). Updated results and pharmacokinetic analysis will be presented. Conclusion: In the ongoing PXD101-CLN-15 study no dose limiting toxicity was determined so far. Clinical efficacy in the form of complete remissions has been demonstrated both of the belinostat monotherapy and of the combination with idarubicin in the 5-d regimen as well as in the CIV regimen. Dose escalation continues as preparation for a phase 2 expansion.

scholarly journals 1093TiP An open-label, multicenter, phase I/II clinical trial of RP1 as a single agent and in combination with nivolumab in patients with solid tumors [IGNYTE]

2021 ◽  
Vol 32 ◽  
pp. S903-S904
Author(s):  
F. Aroldi ◽  
M.R. Middleton ◽  
J.J. Sacco ◽  
M.M. Milhem ◽  
B.D. Curti ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Open Label ◽  
Multicenter Phase

scholarly journals Platform study of genotyping-guided precision medicine for rare solid tumours: a study protocol for a phase II, non-randomised, 18-month, open-label, multiarm, single-centre clinical trial testing the safety and efficacy of multiple Chinese-approved targeted drugs and PD-1 inhibitors in the treatment of metastatic rare tumours

BMJ Open ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. e044543
Author(s):  
Shuhang Wang ◽  
Hui-Yao Huang ◽  
Dawei Wu ◽  
Hong Fang ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Targeted Therapy ◽  
Single Agent ◽  
Solid Tumours ◽  
Targeted Drugs ◽  
Gene Fusions ◽  
Single Centre ◽  
Open Label ◽  
Safety And Efficacy ◽  
Rare Tumours

IntroductionLimited clinical studies have been conducted on rare solid tumours, and there are few guidelines on the diagnosis and treatment, including experiences with targeted therapy and immunotherapy, of rare solid tumours in China, resulting in limited treatment options and poor outcomes. This study first proposes a definition of rare tumours and is designed to test the preliminary efficacy of targeted and immunotherapy drugs for the treatment of rare tumours.Methods and analysisThis is a phase II, open-label, non-randomised, multiarm, single-centre clinical trial in patients with advanced rare solid tumours who failed standard treatment; the study aims to evaluate the safety and efficacy of targeted drugs in patients with advanced rare solid tumours with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (programmed death receptor inhibitor 1, PD-1) inhibitors in patients with advanced rare solid tumours without actionable alterations. Patients with advanced rare tumours who fail standardised treatment and carry actionable alterations (Epidermal growth factor receptor (EGFR) mutations, ALK gene fusions, ROS-1 gene fusions, C-MET gene amplifications/mutations, BRAF mutations, CDKN2A mutations, BRCA1/2 mutations, HER-2 mutations/overexpressions/amplifications or C-KIT mutations) will be enrolled in the targeted therapy arm and be given the corresponding targeted drugs. Patients without actionable alterations will be enrolled in the PD-1 inhibitor arm and be treated with sintilimab. After the patients treated with vemurafenib, niraparib and palbociclib acquire resistance, they will receive combination treatment with sintilimab or atezolizumab. With the use of Simon’s two-stage Minimax design, and the sample size was estimated to be 770. The primary endpoint of this study is the objective response rate. The secondary endpoints are progression-free survival in the targeted treatment group and single-agent immunotherapy group; the duration of response in the targeted therapy and single-agent immunotherapy groups; durable clinical benefit in the single-agent immunotherapy group; and the incidence of adverse events.Ethics and disseminationEthics approval was obtained from the Chinese Academy of Medical Sciences (ID: 20/132-2328). The results from this study will be actively disseminated through manuscript publications and conference presentations.Trial registration numbersNCT04423185; ChiCTR2000039310.

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