scholarly journals Pharmacokinetics of KA2237, a novel selective inhibitor of PI3K-β and PI3K-δ, in patients: A first-in-human study using PK modelling to predict drug concentrations during dose escalation

2021 ◽  
Author(s):  
James Dow ◽  
Graham Trevitt ◽  
Elisabeth Bone ◽  
Kemal Haque ◽  
Loretta Nastoupil
Keyword(s):  
Dose Escalation ◽  
Clinical Studies ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
Selective Inhibitor ◽  
Drug Accumulation ◽  
Clinical Safety ◽  
Once Daily ◽  
Drug Levels ◽  
Drug Concentrations

Aims: KA2237, an oral, potent and selective, inhibitor of the PI3K β and δ isoforms, was evaluated for safety, tolerability and pharmacokinetics (PK) in patients with B-cell lymphoma. KA2237 is metabolised by CYP3A4/5 but also demonstrated mechanism-based inhibition (MBI) of CYP3A4/5. An MBI mechanistic dynamic model was used to predict drug accumulation after repeat dosing of KA2237. This model, along with clinical safety data, was used to guide safe dose escalation. Methods: An open-label, single arm, dose escalation study was carried out in patients, dosed orally with KA2237 at 50, 100, 200 and 400 mg once daily. Complete plasma profiles were obtained on Day 1 and Day 14 of dosing and pre-dose (Cmin) samples were obtained on Days 2-7. The MBI model was validated and used to calculate drug levels and predict potential drug accumulation during dose escalation. Results: KA2237 elimination half-life was around 20-30 h, compatible with once daily dosing regimens. The accumulation of KA2237 was around 4-fold after the highest dose of 400 mg and around 3-fold after administration of 200 mg, which is considered the maximum tolerated dose (MTD). The MBI model accurately predicted this accumulation. Conclusions: Drugs that demonstrate MBI and potential auto-inhibition can be successfully developed, provided that models are developed to assess the extent of accumulation prior to the start of FIH clinical studies. This, along with the close monitoring of drug levels and clinical safety data can be used to guide dose escalation and lead to the safe conduct of clinical studies.

Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3548-3548 ◽  
Author(s):  
T. Mekhail ◽  
T. Rich ◽  
L. Rosen ◽  
F. Chai ◽  
Z. Semic-Suka ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Tumor Cell Migration ◽  
Drug Concentrations ◽  
Arq 197 ◽  
Favorable Safety

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]

scholarly journals Preliminary Results from a Phase I, First-in-Human Study of YY-20394, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5332-5332
Author(s):  
Junyuan Qi ◽  
Yuqin Song ◽  
Bo Jiang ◽  
Jianyong Li ◽  
Meifeng Tu ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Escalation ◽  
Pulmonary Infection ◽  
Cell Lymphoma ◽  
Human Study ◽  
B Cell Lymphoma ◽  
B Cell Malignancies ◽  
Once Daily ◽  
Cancer Hospital

Abstract Introduction: Aberrant activation of the PI3Kδ pathway is associated with increased malignant B-cell proliferation and survival. Recently, several PI3Kδ inhibitors have been reported to play a role in B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL) by mediating abnormal B-cell growth and survival. YY-20394, a novel small molecule, is a highly selective and highly potent PI3Kδ inhibitor. The current study is a phase I, first-in-human, dose escalation study to assess the safety, tolerability, and efficacy of YY-20394 in patients with relapse or refractory B-cell malignant hematological tumor (Chinadrugtrials.org.cn ID: CTR20170995). Methods: Adult patients were eligible for study participation if they had relapsed or refractory lymphoid B-cell malignancies, ECOG ≤2, normal hepatic and renal function, and no autologous hematopoietic stem-cell transplant (HSCT) within 3 months of screening. YY-20394 was given orally once daily until disease progression, unacceptable toxicity, or withdrawal from the study. The protocol was initiated with a single-patient cohort, treated with oral YY-20394 20 mg once daily (QD). Subsequent cohorts used a 3+3 design and evaluated doses of 40-320mg QD. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria. Results: The study enrolment is still ongoing. As of Jul. 14, 2018, total of 10 patients were enrolled. The patients including diffuse large B-cell lymphoma, n=1; follicular lymphoma, n=5; mantle cell lymphoma, n=1; lymphoplasmacytic lymphoma, n=1 and CLL , n=2, received YY-20394 20 mg (n=1), 40 mg (n=3), 80 mg (n=3) or 140 mg/day (n=3) respectively; All the patients had heavy treatment before participating in the current study including BTK inhibitor therapy (n=3) and CAR-T treatment (n=2). All the patient have completed cycle 1 safety observation and no dose-limiting toxicities occurred. The most common nonhematologic TEAEs (all grade [Gr]; Gr ≥3) were LDH elevation (30%; 0%), dizzy (10%; 0%), pneumonia (10%; 10%), alopecia (10%; 0%), and hyperuricemia (10%; 0%). Gr ≥3 hematologic TEAEs were neutropenia (10%) and lymphocythaemia (20%). 1 Serious AEs were reported as grade 3 pulmonary infection after the patient received 2 cycles treatment, it is still unknown if the SAE is related with the study drug. The pulmonary infection has been improved after anti-inflammation treatment. Of 10 patients treated, 71.4% of overall response rate and 100% of disease control rate were achieved in 7 patients who were available for efficacy evaluation, including 1 CR (80 mg, FL) , 4 PR (40 mg, n=2 with FL and CLL respectively; 80 mg, n=2 with FL and DLBCL respectively and 2 SD ( 20 mg with MCL, n=1 and 40 mg with CLL ,n=1 respectively. The PK results demonstrated dose-proportional increase in plasma concentrations. Conclusion: YY-20394 is well tolerated and with promised objective response rates in patients with relapsed or refractory B-cell malignancies. The current first-in-human study for dose escalation and dose expansion is still ongoing. Disclosures Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment.

scholarly journals Clinical and Correlative Results of a Phase 1 Study of Cerdulatinib (PRT062070) a Dual SYK/JAK Inhibitor in Patients with Relapsed/Refractory B Cell Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3929-3929 ◽  
Author(s):  
Paul A Hamlin ◽  
Ian Flinn ◽  
Nina wagner-Johnston ◽  
Jan A Burger ◽  
Glenn Michelson ◽  
...  
Keyword(s):  
Steady State ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Once Daily ◽  
Markers Of Inflammation ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Background: Subsets of B cell lymphomas demonstrate a reliance on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is positioned upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, making it a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways, which can be activated by tumor autocrine signaling loops or by pro-inflammatory cytokines originating from non-malignant infiltrating leukocytes present in the tumor microenvironment. Pre-clinical models demonstrate broad anti-tumor activity with combined SYK and JAK inhibition relative to selective inhibition of these targets alone. Methods: This is a 3+3 dose escalation study with 28-day cycles and doses studied ranging from 15mg to 65mg once daily. PK, PD, and safety were monitored. Clinial response was assessed by standard criteria. The level of inhibition of SYK and JAK was determined by multiple whole blood assays measuring signaling via BCR and receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Results: A total of 36 patients (pt) with CLL/SLL or B cell NHL were dosed. Median age was 67 years (range 23-85) and median prior therapies (tx) was 3 (range 1-8). Treatment emergent AEs of ≥ grade 3 observed deemed related to study drug were: neutropenia (n=2), anemia (n=1), and pneumocystis pneumonia (grade 5, n=1) at 30mg; anemia, AST increase, hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 for each) at 50mg, and diarrhea and fatigue (n=1 for each) at 65mg. The patient with grade 3 AST had tumor progression to the liver. No dose-limiting toxicities (DLT) have been reported to date and cerdulatinib is generally well tolerated. Saturating inhibition of SYK and JAK in circulating lymphocytes (>80% inhibition) and serum inflammation markers (e.g., β2M,CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations achieved at Cmin of the 40mg dose ( 0.6-1µM) at steady state. At the 65mg dose, these parameters were 80-90% inhibited on day 1 of cycle 1 indicating a more immediate effect compared to lower doses. At the 65mg dose, steady state Cmin and Cmax concentrations are approximately 1 and 2µM, respectively, sufficient to induce apoptosis in the majority of B cell lymphoma cell lines tested. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Partial responses (n=4) were observed at 30mg in a pt with del 17p CLL who had relapsed after 6 prior tx; at 45mg a pt with CLL who had received 4 prior tx, and another pt with FL who had received 3 prior tx; and at 65mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6 expression by IHC) who had relapsed approximately 1 year after 1 prior tx. Responses occurred after 2 cycles of tx. Seven total patients have remained on cerdulatinib for over 200 days, including 2 who have been on for a year or more. Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab. Disclosures Michelson: Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Pandey:Portola Pharmaceuticals Inc: Employment. Birrell:Portola Pharmaceuticals Inc: Employment. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Leeds:Portola Pharmaceuticals Inc: Employment. Curnutte:Portola Pharmaceuticals Inc: Employment.

scholarly journals Safety and Early Efficacy Analysis of a Novel Combination of the PARP Inhibitor Veliparib (ABT-888) Plus Bendamustine and Rituximab in Patients with Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1739-1739
Author(s):  
John F. Gerecitano ◽  
Paul Hamlin ◽  
Steven M. Horwitz ◽  
Matthew J Matasar ◽  
Alison J. Moskowitz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Parp Inhibitor ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas

Abstract Background: PARP is overexpressed in many malignancies, and can protect tumor cells from chemotherapy related genetic damage. The PARP inhibitor veliparib (V) enhances the cytotoxicity of several alkylating agents. Since bendamustine (B) is an alkylator with promising clinical activity in a variety of lymphoid malignancies and some solid tumors, we have executed a phase 1b trial combining V with B in patients with solid tumors, lymphomas and multiple myeloma. The dose escalation portion of this study was reported in 2013, and established an MTD of 300 mg bid V in combination with B. We are now completing a cohort expansion of V plus B and rituximab (R) in patients with B-cell lymphomas, concluding this phase 1 trial. We present updated results from lymphoma patients included in the dose escalation portion of the study and new data on the cohort expansion in patients with B-cell lymphomas. Methods: Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for enrollment to the dose escalation portion of this trial. Patients with B-Cell lymphoma (excluding Burkitt and Burkitt-like lymphomas) were treated with B 90mg/m2 IV days 1 and 2, V 300 mg PO bid x7 days and R 375 mg/m2 on day 1 of each 28 day cycle. Planned treatment duration was 6 cycles, with the option of additional cycles in cases of clinical benefit. The cohort expansion was designed to treat 6 patients at the Maximum Tolerated Dose (MTD) of V and B to assess for tolerability with the addition of R. Cohorts were planned with reduced doses of V if dose limiting toxicities (DLT) were seen in >2/6 patients in the first cohort. Results: During the dose escalation phase, 8 patients with lymphoma were treated with B + V. The median number of prior therapies was 4 (range 1-10), and 3 patients received prior B. Six out of 7 evaluable patients responded, with 4 achieving complete remission (CR) and 3 partial remission (PR). Five responding patients have progressed, while one mantle cell lymphoma patient who achieved a CR remains in remission. Median Progression Free Survival in patients with lymphoma treated in the dose escalation phase is 7 months (range 1.8 – 17.4). Five of 6 patients with B-cell lymphoma have been enrolled to the expansion cohort portion of this study (in which R is added to B+V). Toxicities reported in expansion are similar to those from the escalation portion of the study, and include nausea, vomiting and myelosuppression. No DLTs have yet been observed, although one patient did not complete cycle 1 V due to grade 1 nausea before optimal antiemetics could be instituted. All toxicities to date have been grade 1 or 2, with the exception of grade 3 lymphopenia in one patient. Efficacy and additional safety data will be updated in the final presentation. Conclusions: R 375 mg/m2 added to the MTD of V plus B is tolerable in patients with B-cell lymphoma. To date, no additional DLTs have been seen after addition of R to the regimen. This regimen has shown efficacy in lymphoma, although it is unclear if V adds benefit to R/B and a phase II trial will be needed to differentiate the benefit of V. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy.

scholarly journals Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients

2004 ◽  
Vol 48 (7) ◽  
pp. 2388-2393 ◽  
Author(s):  
Jennifer Ford ◽  
Marta Boffito ◽  
Adrian Wildfire ◽  
Andrew Hill ◽  
David Back ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Gradient Centrifugation ◽  
Lymphocyte Subset ◽  
Drug Accumulation ◽  
Color Flow ◽  
Minimum Effective Concentration ◽  
Once Daily ◽  
Drug Concentrations ◽  
Immunodeficiency Virus

ABSTRACT Ritonavir-boosted saquinavir (SQV/r) is currently licensed as a twice-daily regimen. Reducing the pill burden with once-daily dosing may improve adherence. Intracellular concentrations of drugs must be related to the clinical efficacy of protease inhibitors. The aims of the study were to determine the cellular and plasma saquinavir and ritonavir concentrations, to determine the half-lives (t 1/2s) of the drugs in each compartment, and to examine relationships between drug accumulation and lymphocyte subset P glycoprotein (P-gp) expression. Venous blood samples from 12 human immunodeficiency virus-infected patients receiving a hard-gel formulation of SQV/r (1,600/100 mg once daily) were collected at 2, 6, 12, and 24 h after dosing. Peripheral blood mononuclear cells were separated by density gradient centrifugation, and P-gp expression was measured by dual-color flow cytometry. Plasma and intracellular (cell-associated) drug concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The ratio of the intracellular drug area under the concentration-time curve from 0 to 24 h (AUC0-24 h) to plasma drug AUC0-24 h was calculated to determine cellular drug accumulation. The median (range) AUC0-24 h of saquinavir in plasma was 16.2 (5.7 to 39.3) mg · h · liter−1, and that in cells was 46.3 (24.7 to 114.6) mg · h · liter−1. Corresponding ritonavir values were 7.5 (1.5 to 14.6) mg · h · liter−1 and 10.4 (3.2 to 13.7) mg · h · liter−1, respectively. The median accumulation ratios of cellular AUC to plasma AUC for saquinavir and ritonavir were 3.31 (range, 1.49 to 6.69) and 1.46 (range, 0.83 to 4.15), respectively. Significant differences between the plasma and intracellular saquinavir t 1/2s (4.5 h [range, 2.5 to 9.3 h] and 5.9 h [range, 4.0 to 17.7 h]; P = 0.034) and between the plasma and intracellular ritonavir t 1/2s (4.1 h [range, 2.6 to 8.3 h] and 6.2 h [range, 3.9 to 18.6 h]; P = 0.032) were observed. No relationship was observed between the accumulation of saquinavir or ritonavir and lymphocyte subset P-gp expression. The intracellular t 1/2s of saquinavir and ritonavir were longer than the plasma t 1/2s, indicating that intracellular drug may be available at a time when concentrations in plasma are below the minimum effective concentration.

Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13010-e13010
Author(s):  
Helene Senellart ◽  
Jaafar Bennouna ◽  
Nicolas Isambert ◽  
Helene De-Montserrat ◽  
Patrick J. Squiban ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Dose Range ◽  
Safety Data ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Once Daily ◽  
Expansion Cohort ◽  
Initial Starting

e13010 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; >2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.

Initial Safety, Pharmacokinetic and Pharmacodynamic Data from a Phase I Clinical Trial of Systemic C-MYB Antisense Oligodeoxynucleotide in Subjects with Refractory Hematologic Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4033-4033
Author(s):  
Noelle V Frey ◽  
Anna Kalota ◽  
Melissa Potuzak ◽  
Doris Shank ◽  
Cezary R Swider ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Hematologic Malignancies ◽  
Hematopoietic Cell ◽  
Antisense Oligodeoxynucleotide ◽  
Mrna Levels ◽  
Drug Levels ◽  
Qrt Pcr ◽  
Drug Concentrations ◽  
Dose Levels

Abstract BACKGROUND: Conventional treatment options for patients with relapsed hematologic malignancies are both limited and highly toxic driving the pursuit of more tumor specific and less toxic therapies. RNA targeted oligonucleotides are potentially powerful drugs with the ability to silence genes required for malignant hematopoietic cell growth at the post transcriptional level. Studies from our laboratory have validated the c-myb proto-oncogene, which regulates important hematopoietic cell functions and is overexpressed in many hematologic malignancies, as a target for this technology. A prior Phase I trial using a 24 nucleotide phosphorothioated antisense oligodeoxynucleotide targeted to c-Myb mRNA (C-MYB AS ODN) did not identify a maximum tolerated dose (MTD) of the drug. Here we report initial results of a follow up Phase I dose escalation trial using C-MYB AS ODN at higher dose levels than previously studied in subjects with refractory hematologic malignancies. METHODS: C-MYB AS ODN is administered as a 7 day continuous infusion. 5 dose levels ranging from 3mg/kg/day to 12mg/kg/day are planned. Subjects are enrolled using an accelerated dose escalation scheme in which one subject is enrolled on each dose level (DL) with plans to revert to the standard 3+3 design in the event of significant attributable toxcity. C-MYB AS ODN concentrations are measured in peripheral blood (PB) and in mononuclear cells (MNC) by slot blotting at baseline, days 3 and 7 of infusion and two weeks after cessation of infusion. C-myb expression is assessed at these timepoints though QRT-PCR for c-myb RNA. Disease specific assessments of response are measured at predefined timepoints after therapy. RESULTS: 6 subjects, all with refractory acute myelogenous leukemia (AML) have enrolled to date. Escalation through the first 3 DLs occurred without any toxicities. At DL4 (10mg/kg/day) abnormalities have been noted in coagulation assays. The first subject enrolled on DL 4 developed a grade 3 prolongation of the activated partial thromboplastin time (PTT) attributable to drug which returned to normal within 48 hours of drug cessation. Factor levels, DIC parameters and reptilase time were normal. The PTT abnormality was consistent with a “lupus like” inhibitor effect (DRVVT was abnormal and the PTT corrected with the addition of phospholipid in two independent tests.) The 2nd subject treated at DL 4 developed a milder but similar PTT prolongation. The 3rd subject enrolled on DL 4 had a normal PTT throughout therapy. No subjects developed bleeding complications. Plasma and intracellular drug concentrations were dose related (320–640pg/l and 2–80 ng/5×10e6 cells respectively). Peak drug concentrations were found on Days 3–7. By 14 days after infusion, most ODN was cleared from plasma, but remained measurable in MNC at concentrations 30–50% of the maximum value detected. QRT-PCR for c-myb mRNA was performed in 3 subjects. Subject 1’s (DL 1) c-myb mRNA levels gradually decreased from baseline during infusion and nadired two weeks after cessation of infusion. Subjects 3 (DL 3) & 5 (DL 4) had a decrease in c-myb mRNA levels midway through infusion but c-myb RNA levels increased back to baseline by cessation of infusion. To date no subject has had a clinically important response to therapy. Accrual continues for DL 5. CONCLUSIONS: C-MYB AS ODN is detectable in plasma and MNCs of subjects during continuous drug infusion with a steady state reached by day 3 of infusion. Plasma drug levels were markedly reduced 14 days after cessation of infusion but MNC drug levels remained elevated. C-MYB AS ODN at DL 4 (10mg/kg/day) is associated with a PTT prolongation consistent with a “lupus inhibitor” like effect. While encouraging biological activity was identified optimal dose and delivery remain to be established before clinically significant effects can be reasonably expected.

Predictivity/Translatability of Toxicities Observed in Nonclinical Toxicology Studies to Clinical Safety Outcomes in Drug Development: Case Examples

2019 ◽  
Vol 39 (2) ◽  
pp. 141-150
Author(s):  
Nicola J. Stagg ◽  
Hanan N. Ghantous ◽  
Robert Roth ◽  
Kenneth L. Hastings
Keyword(s):  
Drug Development ◽  
Annual Meeting ◽  
Clinical Studies ◽  
Early Termination ◽  
New Drugs ◽  
Clinical Safety ◽  
Case Examples ◽  
Palm Springs ◽  
Starting Dose ◽  
Good Concordance

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article.

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