Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.

186 Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]

Download Full-text

Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6577 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6577-6577 ◽

Cited By ~ 1

Author(s):

Gail J. Roboz ◽

Hanna Jean Khoury ◽

Jamile M. Shammo ◽

Mary Syto ◽

Francis Burrows ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Intensive Therapy ◽

Study Drug ◽

Underlying Disease ◽

Median Number ◽

Open Label ◽

Dose Escalation Study ◽

Multikinase Inhibitor ◽

Dose Levels

6577 Background: TG02 is a novel multikinase inhibitor with a unique spectrum of activity, targeting both the cell cycle regulatory cyclin-dependent kinases (CDKs) 1 and 2 and the transcriptional regulators CDKs 7 and 9. TG02 also inhibits the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5. TG02 kills primary blasts from a variety of hematologic cancers and is curative in the MV4-11 model of FLT3-mutant AML. Methods: This is a first-in-man,single arm, open label, phase I dose escalation trial. The primary endpoints are dose-limiting toxicity (DLT), maximally tolerated dose (MTD ) and recommended phase 2 dose (RP2D). Patients (pts) ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules. Pts had acceptable organ function and ECOG PS 1-2. Definition of DLT was G3-4 AST or ALT ≥7 days, G4 AST or ALT, G4 hyperbilirubinemia, any other NCI CTC G3-4 events not due to underlying disease. Dose levels on arm A were 10mg to 70mg and 15mg-150 mg on arm B. Results: Forty-five pts have received at least one dose of study drug. Median age was 66 years (range, 37-87) and 80% were ECOG 0-1. Disease types enrolled included: AML (80%), high-risk MDS (22%), and CML-BC (3%). The median number of previous regimens was 3 (range, 1-12). The MTD on arm A was defined at 50 mg daily based on 2 DLTs at the 70mg dose level (G4 hyperbilirubinemia, G4 fatigue). Enrollment to arm B has competed dose levels 15 (N=3), 30 (N=3), 50 (N=3), 70 (N=3), 100mg (N=3), and enrollment at 150mg is ongoing without DLT to date. Common drug related adverse events were nausea (42%), vomiting (23%), fatigue (18%), decreased appetite (15%), constipation and diarrhea (13% each). Preliminary PK demonstrated dose proportional increases in exposure and a T1/2 , supporting once daily dosing. Conclusions: The MTD for TG02 has been determined for the daily schedule at 50mg. Enrollment continues on the intermittent schedule. Schedules of every other day and week on/week off dosing will also be evaluated.

Download Full-text

A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16517 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16517-e16517 ◽

Cited By ~ 2

Author(s):

Christos Kyriakopoulos ◽

Channing Judith Paller ◽

Ajit Verma ◽

Karim Kader ◽

Jeff Kittrelle ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Human Study ◽

Study Drug ◽

Maximum Tolerated Dose ◽

Drug Formulation ◽

Clinical Activity ◽

Second Phase ◽

Castration Resistant Prostate Cancer ◽

Dose Escalation Study

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.

Download Full-text

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9533 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9533-9533 ◽

Cited By ~ 2

Author(s):

Michael B. Atkins ◽

John M. Kirkwood ◽

Jedd D. Wolchok ◽

Margaret K. Callahan ◽

Harriet M. Kluger ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Performance Status ◽

Study Drug ◽

Advanced Melanoma ◽

Post Treatment ◽

Dose Escalation Study ◽

Term Survival

9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.

Download Full-text

Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.6043 ◽

2010 ◽

Vol 28 (7) ◽

pp. 1181-1189 ◽

Cited By ~ 73

Author(s):

Josep Tabernero ◽

Andres Cervantes ◽

Fernando Rivera ◽

Erika Martinelli ◽

Federico Rojo ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Metastatic Colorectal Cancer ◽

Dose Escalation ◽

Progression Free Survival ◽

Wild Type ◽

Dose Escalation Study ◽

Tissue Samples ◽

First Line Therapy ◽

Biomarker Analysis

PurposeThis study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC).Patients and MethodsSixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m2initial dose then 250 mg/m2per week; patients in the dose-escalation arms received 400 to 700 mg/m2every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed.ResultsIn subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27Kip1and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response.ConclusionBiomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.

Download Full-text