Phase I study of continuous oral dosing of an irreversible CYP17 inhibitor, abiraterone (A), in castration refractory prostate cancer (CRPC) patients (p) incorporating the evaluation of androgens and steroid metabolites in plasma and tumor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5063-5063 ◽  
Author(s):  
G. Attard ◽  
T. A. Yap ◽  
A. H. Reid ◽  
C. Parker ◽  
M. Barrett ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Clearance ◽  
Secondary Resistance ◽  
Once Daily ◽  
Elimination Half ◽  
Tumor Biopsies ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Post Therapy ◽  
Steroid Precursor

5063 Background: Despite androgen deprivation therapy, recent studies indicate high levels of intra-tumor androgens and continued androgen receptor (AR) signalling in CRPC. Methods: A phase I trial to evaluate the safety and tolerability of A administered once daily at 250, 500, 750, 1,000 and 2,000 mg to chemotherapy-naïve CRPC p. Extensive endocrine evaluation and CTC enumeration were undertaken. Tumor biopsies pre- and post-therapy were evaluated for androgen levels and TMPRSS2/ETS gene translocations. To investigate secondary resistance due to activation of a promiscuous AR by raised precursor steroids upstream of CYP17, all p who progressed were offered combination treatment of A with dexamethasone 0.5mg od (D). Results: 15 p were treated in 3-p cohorts with PSA declines >70% in 9/16 p ( table ) and subsequent expansion of the maximum biologically available dose of 1,000mg (19 p treated to date). All p had progressed on LHRH agonists and antiandrogens, 7/15 on diethylstilboestrol and 7/15 on steroids. No dose limiting toxicities were observed and the only = grade 2 toxicity was reversible hypertension (5 pts) due to CYP17 inhibition. Pharmacokinetics were dose-proportional; mean drug clearance was 803L/hour; mean Vd was 11680L; mean elimination half-life was 10.6 hours. At all dose levels, treatment was associated with increased steroid precursor levels upstream of CYP17, including up to a 300-fold rise in corticosterone levels, as well as loss of detection of adrenal androgens. Circulating testosterone levels were in the castrate range (<50 ng/dl) at baseline, rapidly becoming undetectable (<1 ng/dl) in all p. Conclusion: A can be safely administered to CRPC pts with CYP17 suppression and important anti-tumor activity suggesting that at least 60% of CRPC are still hormone driven. Phase II evaluation of 1,000 mg is ongoing. [Table: see text] [Table: see text]

A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide [Revlimidä (R), CC-5013] in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5136-5136 ◽  
Author(s):  
C. Gerecke ◽  
S. Knop ◽  
M.S. Topp ◽  
S. Kotkiewitz ◽  
H. Gollasch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Refractory Multiple Myeloma ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Introdution: Lenalidomide (Revlimid™) is Celgene’s lead clinical compound in a new group of drugs called IMiDs, which have immunomodularory properties. The drug has been evaluated in phase-I, II, and III clinical trials for the treatment of multiple myeloma (MM). Lenalidomide shows substantial anti-tumor activity in patients with refractory or relapsed MM and significantly prolongs time to tumor progression (TTP) compared to standard therapy in these patients. Lenalidomide was well tolerated in these trials, the only dose limiting toxicity in a phase-I trial was myelosuppression. In order to further improve therapeutic efficacy and to overcome drug resistance we are currently evaluating Lenalidomide (Revlimid™) in combination with doxorubicin and dexamethasone (RAD) for the treatment of patients with refracrory or relapsed MM in a phase-I/II trial. Methods: Patients with relapsed or refractory multiple myeloma recieve a fixed dose of either 10 mg or 15 mg Revlimid Revlimid™ given daily for 21 days (d 1–21) in combination with doxorubicin (adriamycin) and dexamethasone, to be repeated on day 29. Three dose levels of doxorubicin (adramycin) are planned: 4 mg/m2 day 1–4, 6 mg/m2 day 1–4 and 9 mg/m2 day 1–4. 40 mg dexamethasone is given orally day 1–4 and day 17–20 at a fixed dose. 3– 6 cycles are applicated unless severe toxicity or disease progression occurs. Results: RAD treatment was well tolerated at dose level 1 and dose level 2. Therefore, current dose escalation is continued. All patients treated at the first two dose levels (6/6) responded to RAD treatment. Further updated results on this trial will be presented.

Phase I Study of Eltrombopag for Promoting Thrombopoiesis in Patients Undergoing Stem Cell Transplantation After Total Body Irradiation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3295-3295 ◽  
Author(s):  
Jane L. Liesveld ◽  
Gordon L. Phillips ◽  
Michael W. Becker ◽  
Louis Constine ◽  
Jonathan Friedberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Dose Level ◽  
Total Body Irradiation ◽  
Conditioning Regimen ◽  
Once Daily ◽  
Total Body ◽  
Dose Levels

Abstract Abstract 3295 Purpose: Prolonged intervals of thrombocytopenia are common after hematopoietic stem cell transplantation (HSCT), and platelet transfusions are the only effective therapy. Risk of thrombocytopenia is greater in patients (pts) receiving total body irradiation (TBI) in their conditioning regimen. Eltrombopag (ePag) is a small-molecule, nonpeptide oral agent that functions as an agonist of the thrombopoietin receptor. It is approved by FDA for the treatment of chronic ITP and is being developed as a treatment for thrombocytopenia of other various etiologies. We report results of an ongoing Phase I clinical trial assessing the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of once daily oral ePag in pts undergoing HSCT with a conditioning regimen containing TBI ≥ 400 cGy. Methods: A Phase I dose-escalation clinical trial was conducted to evaluate the safety and PK of ePag at 4 different dose levels: 75, 150, 225, and 300 mg, once daily for 27 days, starting 24–48 hours post HSCT to eligible pts ≥18 yrs old. Pts with various indications for stem cell transplantation, KPS ≥70%, and TBI ≥ 400 cGy were eligible. Pts receiving either an autologous (Auto) or allogeneic (Allo) HSCT from a sibling, related donor, or matched unrelated donor (MUD) were eligible. Stem cells from peripheral blood (PBSC) or bone marrow were permitted; however, cord blood transplant was not permitted. Pts at risk of thromboembolism, or with a history of thromboembolic disease in the preceding 6 months, were excluded. PK sampling was obtained over a 24 h period after the first dose of ePag, as well as during the second week of treatment (steady-state). Results: As of July 1 2011, a total of 10 subjects (4 AML, 2 lymphoma, 1 CML, 1 MDS, 1 myelofibrosis, and 1 CLL/SLL) were enrolled, and 9 completed protocol treatments. All 9 were PBSC transplants with 6 MUD, 2 Allo and 1 Auto. Three subjects were completed at each dose level up to 225 mg. Enrollment is continuing at the 300 mg dose level. To date, 6/9 are alive while 3/9 died of non-relapse related causes (CMV pneumonitis and respiratory failure in 1, and steroid refractory GI GvHD in 2, f/u interval: 4.4 – 6.9 mo). No dose limiting toxicities (DLTs) have been observed. Most common adverse events up to 225 mg dose level were related to standard stem cell transplantation, which included low blood counts, fatigue, headache, diarrhea, nausea, peripheral edema, hypoalbuminemia, hyperglycemia, hypocalcemia, and hypomagnesemia. There were 9 SAEs observed in 5 pts, which included infection (3/9), pulmonary embolism (PE) (1/9), acute renal failure (2/9), gastrointestinal (2/9), and ARDS (1/9). Most SAEs were considered unrelated or unlikely related to ePag treatment except for the PE, which was considered possibly related to ePag but not considered a DLT. This subject had other risk factors for PE and the PE occurred 9 days after ePag had stopped at a platelet count of 252K. Time to platelet engraftment and number of platelet transfusions were documented for each enrolled pt. PK sampling demonstrated a dose dependent increase in plasma concentration of ePag (Figure 1). PK parameters for the 75, 150, and 225 mg dose levels are summarized in Table 1. Conclusions: 27-day once daily dosing of ePag to enhance platelet recovery for post-transplant thrombocytopenia is well tolerated, with no DLTs observed up to the 225 mg dose level to date. Most AEs were transplant related. PK and the plasma exposure of ePag appears dose proportional over the studied dose range after single-dose and steady-state administration. Once-daily administration of up to 225 mg ePag for the transplant population receiving TBI ≥ 400 cGy as part of the conditioning regimen appears to be safe and well tolerated. Acknowledgment: The study is supported by Biomedical Advanced Research and Development Agency (BARDA), and by GlaxoSmithKline who also provided the study drug. Disclosures: Off Label Use: Promacta (eltrombopag) is an oral TPO Receptor agonist approved for the treatment of chronic ITP. The study being reported in this abstract is a phase I MTD study to evaluate eltrombopag for promoting thrombopoiesis in patients undergoing Stem Cell Transplantation after Total Body Irradiation. Dawson:GlaxoSmithKline: Employment.

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Dose Selection ◽  
Normal Tissues ◽  
Tumor Biopsies ◽  
Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A Children's Oncology Group Phase I Consortium study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10023-10023
Author(s):  
S. L. Berg ◽  
H. Russell ◽  
M. Cairo ◽  
A. M. Ingle ◽  
P. C. Adamson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Fixed Dose ◽  
Ischemic Event ◽  
Thromboembolic Risk ◽  
Once Daily ◽  
Antiproliferative Effects ◽  
Dose Levels

10023 Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults. No significant financial relationships to disclose.

A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13599-e13599 ◽  
Author(s):  
Khurum Hayat Khan ◽  
Li Yan ◽  
Janusz Mezynski ◽  
Amita Patnaik ◽  
Victor Moreno ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Akt Inhibitor ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Simultaneous Inhibition ◽  
Investigational Agents ◽  
Dose Levels

e13599 Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer. [Table: see text]

Evaluation of tumor and circulating cell free (cf) DNA mutations in women with hormone refractory metastatic breast cancer (MBC) enrolled in a phase I study of Z-endoxifen (MC093C).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1043-1043
Author(s):  
Matthew P. Goetz ◽  
Vera J. Suman ◽  
Joel M. Reid ◽  
Donald W. Northfelt ◽  
Sarah A Burhow ◽  
...  
Keyword(s):  
Phase I ◽  
Sequence Data ◽  
Metastatic Breast ◽  
Dna Mutations ◽  
Targeted Ngs ◽  
Prognosis And Prediction ◽  
Er Positive ◽  
Hormone Refractory ◽  
Tumor Biopsies ◽  
Dose Levels

1043 Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.

A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3501-3501 ◽  
Author(s):  
A. J. Wagner ◽  
D. H. Von Hoff ◽  
P. M. LoRusso ◽  
R. Tibes ◽  
K. E. Mazina ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Ca 125 ◽  
Dose Escalation Study ◽  
A Cell ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Dose Proportional

3501 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade >3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for >176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented. [Table: see text]

Phase I Study of a Novel Oral JAK-2 Inhibitor SB1518 In Patients with Relapsed Lymphoma: Evidence of Clinical and Biologic Activity In Multiple Lymphoma Subtypes.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2830-2830 ◽  
Author(s):  
Anas Younes ◽  
Michelle A. Fanale ◽  
Peter McLaughlin ◽  
Amanda Copeland ◽  
Joy Zhu ◽  
...  
Keyword(s):  
Phase I ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Phase I Study ◽  
Prior Treatment ◽  
Once Daily ◽  
Treatment Regimens ◽  
Relapsed Lymphoma ◽  
Dose Levels ◽  
Stat Pathway

Abstract Abstract 2830 Introduction: The Janus kinase 2 (JAK2) signal transducers and activators of transcription (STAT) pathway plays an important role in the proliferation and pathogenesis of hematological malignancies. In vitro inhibition of JAK2 results in antiproliferative activity in a variety of lymphoma cell lines. We have completed dose-escalation in a Phase-I study of the novel small molecule JAK2 inhibitor SB1518 in patients with relapsed Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL). Patients and Methods: The primary objectives were to examine the safety and efficacy of SB1518 in this patient population. Patients were eligible if they had relapsed or refractory HL or NHL of any type except Burkitt's, any number of prior treatment regimens as well as adequate organ function and performance status. They were excluded if they had HIV infection or CNS lymphoma. Cohorts of 3–6 patients received escalating dose levels of SB1518 orally once daily for 28-day cycles. Response was first evaluated after 8 weeks (2 cycles) of therapy. Results: Thirty patients have been enrolled (14 HL, 3 mantle cell [MCL], 8 follicular [FL], 4 diffuse large B-cell [DLBCL], 1 small lymphocytic [SLL]). Patients have been treated orally once daily at 5 dose levels, 100 mg (n=3), 200 mg (n=7), 300 mg (n=6), 400 mg (n=7) and 600 mg (n=7). Twenty of 30 patients were male and 10 were female. 28 have received SB1518 of which twenty-six are evaluable for tumor response and all 28 are evaluable for safety. The median number of prior treatment regimens was 5.5 (range 2–15), Prior treatment included an autologous transplant in 12 patients and an allogeneic stem cell transplant in 2. Treatment was well tolerated, with the most common Grade 1–2 toxicities (≥10% in frequency) being: constipation 43% (n=12), diarrhea 43% (n=12), pyrexia 32% (n=9), nausea 29% (n=8), cough and fatigue 21% (n=6), decreased appetite 18% (n=5) and anemia, anorexia, chills, dyspnea, headache, peripheral edema, peripheral neuropathy 11% (n=3). Grade 3–4 toxicities included: neutropenia 7% (n=2), abdominal distension, anemia, bacteremia, cellulitis, cerebral vascular accident, dyspnea, fatigue, hyperbilirubinemia, hypotension, lymphopenia, musculoskeletal pain, peripheral edema, pneumonia, pulmonary embolism, pyelonephritis, retroperitoneal hemorrhage and thrombocytopenia 4% (n=1). Dose escalation has been halted at 600 mg without identification of the MTD and enrollment continues in an expanded 600 mg cohort to confirm the recommended Phase II dose. There were no CRs, 3 patients had PRs (2 MCL, 1 FL at 300, 400, 600 mg), and 13 patients had SD (7 FL, 5 HL, 1 SLL), with the majority of responses sustained for >2 months. Of the patients with SD 7/13 had reduction in tumor mass of 4–46%. Serial plasma samples were collected for PK analysis. Pharmacologically active concentrations were achieved at the lowest dose level (100 mg). Dose related increases in AUC were seen on C1D1 and C1D15 up to 400mg. The terminal half-life was 1–3 days, and mean Tmax ranged between 5–9 hours. The effect of drug treatment on pJAK2, pSTAT3, and pSTAT5 was examined in PBMCs and whole blood before and after the first dose of SB1518. SB1518 inhibited the JAK/STAT pathway as early as 4 hrs after the first dose at all dose levels. Plasma was collected at each cycle to assess changes in cytokines, chemokines and growth factors. Data show marked reductions in inflammatory cytokines such as IFNalpha, as well as in PDGFalpha and beta, VEGF and RANTES in >50% of patients with samples tested (SB1518 dose levels of 100, 200, and 300 mg). Samples from higher dose levels are being tested and results will be correlated to response. Efficacy and biomarker data confirm the activity of SB1518 in multiple lymphoma subtypes and show the safety of chronic administration at doses up to 600 mg daily. Collectively these data suggest that targeting the JAK2 pathway has therapeutic value in patients with relapsed lymphoma. A Phase II trial of SB1518 in selected lymphomas is being initiated. Disclosures: Zhu: S*BIO: Employment.

scholarly journals Preliminary Results from a Phase I Study of HMPL-523, a Selective Oral Syk Inhibitor, in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2432-2432
Author(s):  
Paolo Strati ◽  
Dominik Chraniuk ◽  
Eva González-Barca ◽  
Michal Taszner ◽  
Rathi Pillai ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Publicly Traded ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Background: Spleen tyrosine kinase (Syk) plays an integral role in B-cell receptor signaling critical in the development and survival of several subtypes of lymphoma. HMPL-523 is a selective, oral Syk inhibitor that has shown strong anti-tumor efficacy in xenograft models of B-cell and T-cell lymphoma. HMPL-523 had a manageable safety profile and demonstrated anti-tumor activity in a phase I study of lymphoma patients in China (NCT02857998). Here, we report the safety and preliminary anti-tumor activity of HMPL-523 in the dose escalation phase of a phase 1 study of relapsed/refractory lymphoma patients in the United States and Europe (NCT03779113). Methods: The primary objectives of the phase I study were to evaluate the safety and tolerability of HMPL-523 and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary objectives were to assess the pharmacokinetics (PK) and evaluate the preliminary efficacy of HMPL-523. Eligible patients had histologically confirmed lymphoma, exhausted all approved therapy options, and had good organ function, including creatinine clearance ≥ 40 ml/min by Cockcroft-Gault, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL, and hemoglobin ≥ 8.0 g/dL. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (AEs) were assessed per NCI CTCAE v5.0. Treatment responses were assessed by Lugano criteria at weeks 8, 16, and 24, and then every 12 weeks. Patients received HMPL-523 treatment daily in 28-day cycles until disease progression or unacceptable toxicity. Results: As of July 15, 2021, 21 patients had been enrolled and dosed with HMPL-523 at one of six dose levels (100 to 800 mg once daily). Baseline tumor subtypes included Hodgkin lymphoma (HL; n=5); diffuse large B-cell lymphoma (DLBCL; n=4); follicular lymphoma (FL; n=4); marginal zone lymphoma (MZL; n=2); and 1 patient each with mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mixed HL/DLBCL, and Richter's transformation. Patients were predominantly Caucasian (90.5%) and male (71.4%). The median age was 61 years (range 27 to 89 years) and 71.4% had an ECOG performance status of 1. The median lines of prior therapy was 4 (range 2 to 17). The majority of patients had prior anti-CD20 antibody exposure (71.4%), and four patients (19%) received prior Bruton tyrosine kinase inhibitors. Five patients continue to receive study treatment. The most frequently reported treatment emergent AEs were aspartate aminotransferase increase (23.8%), anemia (23.8%), neutropenia (19%), hyponatremia (19%), creatinine increase (19%), and nausea (19%). The most common grade ≥ 3 AEs were neutropenia (14.3%), hyponatremia (14.3%), and anemia (9.5%). Three dose limiting toxicities were observed: 1 in the 100 mg cohort (grade 3 confusion) and 2 in the 800 mg cohort (grade 3 fever and grade 3 alanine aminotransferase increase). The dose was deescalated to 700 mg, which was determined to be the MTD and RP2D. Among 17 efficacy evaluable patients, 2 patients (1 HL, 1 FL) dosed at 600 mg and 800 mg (reduced to 600 mg due to toxicity) achieved complete response, and 1 patient (dose increased from 400 to 600 mg) achieved partial response (FL). Stable disease was observed in 5 (29.4%) patients (2 DLBCL, 1 MCL, 1 SLL, 1 PTCL). At steady state, HMPL-523 showed approximately dose proportional PK over the daily dose range of 100 to 700 mg. Conclusions: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 700 mg and demonstrated proof of activity at dose levels of 400 mg or higher in heavily pre-treated patients. The dose expansion phase of the study will evaluate safety and efficacy in patients with multiple subtypes of B-cell and T-cell lymphoma at the RP2D of 700 mg. Updated safety, PK, and anti-tumor activity will be presented. Disclosures Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. González-Barca: Roche: Honoraria, Other: Travel; Kyowa Kirin: Consultancy; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Taszner: Roche, Takeda: Consultancy, Other: Travel. Pillai: HUTCHMED: Current Employment. Chien: HUTCHMED: Current Employment, Current equity holder in publicly-traded company. Nanda: HUTCHMED: Current Employment, Current equity holder in publicly-traded company, Other: Travel. Rudinski: HUTCHMED: Current Employment. Jayaprakash: HUTCHMED, Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astrazeneca: Current equity holder in publicly-traded company. Hahka-Kemppinen: HUTCHMED: Current Employment, Current holder of individual stocks in a privately-held company; Eli Lilly: Current holder of individual stocks in a privately-held company. Kania: HUTCHMED: Current Employment, Current equity holder in publicly-traded company.

A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
M. G. Fakih ◽  
L. Pendyala ◽  
K. Toth ◽  
P. Creaven ◽  
N. Soehnlein ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Stable Disease ◽  
Phase I Study ◽  
Fixed Dose ◽  
Combination Methods ◽  
Disease Stabilization ◽  
Thymidilate Synthase ◽  
Tumor Biopsies ◽  
Dose Levels

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.

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