Phase I dose-escalation study of pasireotide LAR in patients with advanced neuroendocrine tumors.

e15126 Background: Somastatin analogs (SSA), including octreotide and lanreotide, bind predominantly to somatostatin receptor (SSTR) 2 and form the foundation of treatment for symptomatic neuroendocrine tumors (NET). Pasireotide, a novel SSA with a broad binding affinity (SSTR 1-3 and 5), is being explored for treatment of NET. A phase 1 dose-escalation study (NCT01364415) of pasireotide long-acting release (LAR; starting dose of 80 mg) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) and to characterize safety, tolerability, pharmacokinetics, and efficacy in pts with advanced NET. Methods: Pts with advanced, well- or moderately differentiated NET received pasireotide LAR beginning at a dose of 80 mg q28d. Successive cohorts will receive doses (up to 220 mg) guided by a Bayesian logistic regression model until MTD/RP2D is reached. Results: To date, 15 pts have been treated at 80 mg (n=6) and 120 mg (n=9). Median age is 59 (44-76) years. Primary tumor sites include small intestine (40%), pancreas (20%), and lung (13.3%). All pts received prior antineoplastic therapy; 93% received prior SSA. Median number of cycles of pasireotide was 6.68 (2-14) (1 cycle=28 days). 10 (67%) pts remain on treatment: 3 on 80 mg and 7 on 120 mg. 5 (33%) have discontinued (disease progression, 2 pts; withdrew consent, 2 pts; adverse event [AE], 1 pt). Median plasma concentrations of pasireotide increased with dose. No dose-limiting toxicities have been reported. Most frequent AEs were similar in both dose groups and included hyperglycemia (87%), diarrhea (53%), abdominal pain (47%), nausea (40%), anemia (33%), and fatigue (33%). Most AEs were mild/moderate. 2 pts (1 in each group) had grade 3 hyperglycemia. 4 (27%) and 2 (13%) pts had HbA1C increase from <6.5% at baseline to 6.5-<8% and ≥8%, respectively. 13 (87%) pts had radiographically stable disease as best response. More pts at 120 mg (50%) vs 80 mg (33%) achieved ≥50% reduction in chromogranin A. Conclusions: Pasireotide LAR up to 120 mg appears to be well tolerated in patients with advanced NET. The study is ongoing. Pasireotide represents a promising therapy for pts with NET. Clinical trial information: NCT01364415.

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Phase 1 dose escalation study of seribantumab (MM-121), an anti-HER3 monoclonal antibody, in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-021-01145-y ◽

2021 ◽

Author(s):

Crystal S. Denlinger ◽

Vicki L. Keedy ◽

Victor Moyo ◽

Gavin MacBeath ◽

Geoffrey I. Shapiro

Keyword(s):

Monoclonal Antibody ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Objective Response ◽

Growth Factor Receptor ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Clinical Trial Registration ◽

Best Response

SummaryBackground Overactivation of human epidermal growth factor receptor 3 (HER3) triggers multiple intracellular pathways resulting in tumor cell survival. This Phase 1 study assessed the safety, efficacy, and pharmacokinetics (PK) of seribantumab, a fully human anti-HER3 monoclonal antibody. Methods Adult patients with advanced or refractory solid tumors were treated in six dose cohorts of seribantumab: 3.2, 6, 10, 15, or 20 mg/kg weekly, or 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose (40/20 mg/kg) using a modified 3 + 3 dose escalation strategy with cohort expansion. Primary objectives were identification of a recommended Phase 2 dose (RP2D) and determination of objective response rate. Secondary objectives were assessment of safety, dose-limiting toxicities, and PK. Results Forty-four patients (26 dose escalation; 18 dose expansion) were enrolled. Seribantumab monotherapy was well tolerated with most adverse events being transient and mild to moderate (grade 1 or 2) in severity; maximum tolerated dose was not reached. The highest dose, 40/20 mg/kg, was identified as RP2D. Best response was stable disease, reported in 24% and 39% of patients during the dose escalation and expansion portions of the study, respectively. Seribantumab terminal half-life was ≈100 h; steady state concentrations were reached after 3–4 weekly doses. Conclusions Seribantumab monotherapy was well tolerated across all dose levels. Safety and PK data from this study support further seribantumab investigations in genomically defined populations.Clinical trial registration NCT00734305. August 12, 2008.

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Phase 1 Dose Escalation Study of Seribantumab (MM-121), an anti-HER3 Monoclonal Antibody, in Patients with Advanced Solid Tumors

10.21203/rs.3.rs-484551/v1 ◽

2021 ◽

Author(s):

Crystal Denliger ◽

Vicki L Keedy ◽

Victor Moyo ◽

Gavin MacBeath ◽

Geoffrey I Shapiro

Keyword(s):

Monoclonal Antibody ◽

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Objective Response ◽

Growth Factor Receptor ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Clinical Trial Registration ◽

Best Response

Abstract BACKGROUND: Overactivation of human epidermal growth factor receptor 3 (HER3) triggers multiple intracellular pathways resulting in tumor cell survival. This Phase 1 study assessed the safety, efficacy, and pharmacokinetics (PK) of seribantumab, a fully human anti-HER3 monoclonal antibody.METHODS: Adult patients with advanced or refractory solid tumors were treated in six dose cohorts of seribantumab: 3.2, 6, 10, 15, or 20 mg/kg weekly, or 40 mg/kg loading dose followed by 20 mg/kg weekly maintenance dose (40/20 mg/kg) using a modified 3+3 dose escalation strategy with cohort expansion. Primary objectives were identification of a recommended Phase 2 dose (RP2D) and determination of objective response rate. Secondary objectives were assessment of safety, dose-limiting toxicities, and PK.RESULTS: Forty-four patients (26 dose escalation; 18 dose expansion) were enrolled. Seribantumab monotherapy was well tolerated with most adverse events being transient and mild to moderate (grade 1 or 2) in severity; maximum tolerated dose was not reached. The highest dose, 40/20 mg/kg, was identified as RP2D. Best response was stable disease, achieved by 24% and 39% of patients during the dose escalation and expansion portions of the study, respectively. Seribantumab terminal half-life was ≈100 hours; steady state concentrations were reached after 3–4 weekly doses. CONCLUSIONS: Seribantumab monotherapy was well tolerated across all dose levels. Safety and PK data from this study support further seribantumab investigations in genomically defined populations. CLINICAL TRIAL REGISTRATION: NCT00734305.DATE OF REGISTRATION: August 12, 2008.

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PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: A phase 1 dose escalation study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3019 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3019-3019

Author(s):

Jordi Rodon Ahnert ◽

Cesar Augusto Perez ◽

Kit Man Wong ◽

Michael L. Maitland ◽

Frank Tsai ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Urothelial Cancer ◽

Phase 1 ◽

Dose Range ◽

Median Number ◽

Splicing Factor ◽

Dose Escalation Study ◽

Study Objective ◽

Dose Dependent

3019 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple substrates known to be dysregulated in cancer, including components of the spliceosome machinery. PF-06939999 is a selective small-molecule inhibitor of PRMT5. Here we report the safety, PK, PD, and preliminary activity of PF-06939999 in patients (pts) with selected advanced/metastatic solid tumors. Methods: This phase 1 dose escalation trial (NCT03854227) enrolled pts with solid tumor types marked by potential frequent splicing factor mutations, including advanced/metastatic endometrial cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), urothelial cancer, cervical cancer, or esophageal cancer. PF-06939999 monotherapy was continuously administered orally QD or BID in 28-day cycles. A Bayesian Logistic Regression Model was used to inform dose level decisions. Primary objectives were to assess dose limiting toxicities (DLTs), AEs and laboratory abnormalities. Tumor response was assessed using RECIST v1.1. PK and PD were assessed by determining PF-06939999 plasma concentration after dosing and changes in plasma levels of symmetric di-methyl arginine (SDMA), the product of PRMT5 enzymatic activity. Results: 28 pts received PF-06939999 at doses from 0.5-12 mg daily (QD or BID) during dose escalation. Median number of cycles was 2 (range, 1-13). Most were female (54%) with a median age of 61.5 (range, 32-84) y. Median number of prior therapies was 4. Overall, 4/24 (17%) pts reported DLTs: thrombocytopenia (n=2, 6 mg BID); anemia (n=1, 8 mg QD); and neutropenia (n=1, 6 mg QD). Treatment-related AEs occurred in 24 (86%) pts. Most common (≥20%) treatment-related AEs across all cycles were anemia (43%), thrombocytopenia (32%), dysgeusia, fatigue and nausea (29% each). Grade ≥3 treatment-related AEs included anemia (25%), thrombocytopenia (21%), fatigue, neutropenia and lymphocyte count decreased (4% each). One pt (6mg BID) had Grade 4 treatment-related thrombocytopenia. All cytopenias were dose-dependent and reversible with dose modification. No pts discontinued treatment for treatment-related toxicity. There were no treatment-related deaths. Exposure to PF-06939999 increased with doses in the dose range tested. Plasma SDMA was reduced at steady state (58.4-87.5%), indicating robust PD target inhibition. Two pts had confirmed partial response (HNSCC and NSCLC). 6 mg QD was identified as the recommended monotherapy dose for expansion. Conclusions: PF-06939999 showed dose-dependent and manageable toxicities in this phase 1 dose escalation study. Objective tumor responses were observed in pts with HNSCC and NSCLC. Analysis of archival tissue for the presence of splicing factor mutations and other potential predictive biomarkers is ongoing. Enrollment to part 2 dose expansion is ongoing in pts with NSCLC, HNSCC and urothelial cancer. Clinical trial information: NCT03854227.

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ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.105 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi28-vi28

Author(s):

Matthias Holdhoff ◽

Martin Nicholas ◽

Richard Peterson ◽

Oana Danciu ◽

Stefania Maraka ◽

...

Keyword(s):

Dose Level ◽

Dose Escalation ◽

Anaplastic Astrocytoma ◽

Caspase 3 ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Data ◽

Dose Escalation Study ◽

Level 1 ◽

Level 2

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

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A Phase 1 Dose Escalation Study of a Fully Human, Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12) in Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3575.3575 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3575-3575 ◽

Cited By ~ 8

Author(s):

William Bensinger ◽

Sundar Jagannath ◽

Pamela S. Becker ◽

Kenneth C. Anderson ◽

Edward A. Stadtmauer ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Level ◽

Ex Vivo ◽

Phase 1 ◽

Safety Evaluation ◽

Median Number ◽

Maximum Tolerated Dose ◽

Dose Escalation Study ◽

Myeloma Cells ◽

Dose Levels

Abstract HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo (Tai, Y et al. Cancer Res2005; 65(13): 5898–5906). This ongoing phase 1 study will determine the maximum tolerated dose of CHIR-12.12 in multiple myeloma patients (pts) who are relapsed or refractory after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly for 4 weeks. Each dose group will enroll 3–6 pts to evaluate safety, pharmacokinetics (PK) and clinical response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg. Median patient age is 65 yrs (46–81 yrs); median number of prior therapies is 3 (2–12). No dose limiting toxicity (DLT) occurred at the 1mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia occurred in 1 pt. No other grade 3 and 4 lab abnormalities and adverse events have been reported. In 7 pts with available data, infusions were well tolerated, with easily managed grade 1–2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level. At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth infusion on Day 22 was 126.1 mg/mL(range 52 – 195 ug/mL) and HCD122 levels were measurable up to Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from 28 to 109 mg/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for >23 weeks and two had progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9 and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD terminated the study before final safety evaluation, and must be replaced before assessment of the 3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma activity. Enrollment is continuing to determine MTD.

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Phase 1 Dose Escalation Study of the Monoclonal Antibody Against the Insulin Like Growth Factor I Receptor CP-751,871 in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v110.11.1171.1171 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1171-1171 ◽

Cited By ~ 2

Author(s):

Martha Q. Lacy ◽

Melissa Alsina ◽

Luisa Roberts ◽

Rafael Fonseca ◽

Carrie Melvin ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Growth Factor ◽

Dose Escalation ◽

Therapeutic Approach ◽

Phase 1 ◽

Median Number ◽

Insulin Like Growth Factor ◽

Dose Escalation Study ◽

Igf I

Abstract Background: CP-751,871, a fully human IgG2 subtype monoclonal antibody, is a potent and specific inhibitor of the insulin- like growth factor type I receptor (IGF-IR). The IGF-IR regulates the growth, survival, adhesion and invasiveness of multiple myeloma cells. High IGF-IR expression is observed in poor-prognostic subtypes of multiple myeloma and its inhibition has been long proposed as a potential therapeutic approach for treatment of this disease. Methods: A phase 1 dose escalation study was conducted to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic (granulocyte surface IGF-IR expression and serum IGF-I levels) properties of CP-751,871 in patients with multiple myeloma. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase including those less than complete remission to autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 47 patients were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/Kg. Median patient age was 60 years. Median number of previous regimens was 4 (range 1–8). CP-751,871 was given as an IV infusion on Day 1 of 4-week cycles. Patients with a suboptimal response to CP-751,871 alone were eligible to receive CP-751,871 in combination with either oral dexamethasone and/or rapamycin at the discretion of the investigator. Twenty-seven patients received CP-751, 871 in combination with dexamethasone, while four patients received rapamycin in combination with either CP-751,871 or CP-751,871 and dexamethasone. Median number of treatment cycles was 3 (range 1–16). Ten patients were dosed at the highest cohort of 20 mg/Kg. No CP-751,871 related dose limiting toxicities were identified. Grade 3 toxicities were all observed at the 20 mg/Kg cohort (1 hyperglycemia, 1 anemia, 1 AST increase, 1 accidental fall, 1 muscle weakness). Plasma CP-751,871 exposure increased with dose, and the pharmacokinetic characteristics were consistent with target-mediated disposition. Granulocyte IGF-IR expression was maximally down-regulated for the entire duration of the dosing period at doses ≥1.5 mg/kg, indicating a saturation of circulating targets. CP-751,871 also led to a dose-dependent increase in circulating IGF-I concentrations. Tumor response was assessed according to Blade criteria. Two remissions and 4 partial remissions were reported in patients treated with different doses of CP-751,871 in combination with dexamethasone. Interestingly, the 2 patients with remission were previously found to be refractory to dexamethasone treatment. Conclusions: These data indicate that CP-751,871 is well tolerated either as a single agent or in combination with dexamethasone. Furthermore, CP-751,981 in combination with dexamethasone, may constitute a novel and effective therapeutic approach for patients with multiple myeloma.

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Phase 1 study of a focal adhesion kinase (FAK) inhibitor PF-00562271 in patients (pts) with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3527 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3527-3527 ◽

Cited By ~ 11

Author(s):

L. L. Siu ◽

H. A. Burris ◽

L. Mileshkin ◽

D. R. Camidge ◽

D. Rischin ◽

...

Keyword(s):

Antitumor Activity ◽

Dose Escalation ◽

Phase 1 ◽

Plasma Concentrations ◽

Sensory Neuropathy ◽

Competitive Inhibitor ◽

Dose Escalation Study ◽

Tumor Biopsies ◽

Oral Doses ◽

Pet Scans

3527 Background: PF-00562271 is a potent ATP-competitive inhibitor of FAK and, to a lesser extent, Pyk2. FAK transduces signaling from integrins and growth factors to modulate multiple properties important in neoplasia, including tumor cell invasion, proliferation and survival. Structure-activity relationships and preclinical antitumor activity are reported (W.G. Roberts et al, Proc AACR, 2007). Methods: Phase 1 dose-escalation study of PF-00562271 given as twice daily oral doses in 21 day cycles. Endpoints included safety, tolerability, PK, PD (serial tumor biopsies) and antitumor activity. PD was also evaluated by tumor glucose metabolism using FDG-PET. Dose escalation was performed in sequential cohorts of 3–6 pts. Results: 32 pts received 5 mg up to 105 mg BID with demographics M:F = 10:22; median age 60 (range 38–80). Primary tumor sites: colorectal (10), breast (4), neuroendocrine (2), lung (2), gastric (2), SCC (2), ovary (2), others (8). A total of 136 cycles have been administered, median = 3.2, range = 1–10+. Adverse events (AEs) possibly related to PF-00562271 in over 10% of pts included nausea, vomiting, fatigue, anorexia, abdominal pain, diarrhea, headache, sensory neuropathy, rash, constipation, dizziness. AEs were generally CTC grades 1–2 and reversible. Cmax and AUC increased dose-dependently, and AUC accumulated over 6-fold by day 14. Doses over 15 mg BID produced steady-state plasma concentrations, exceeding target efficacious levels predicted from preclinical models. On day 14, PET scans in one pt demonstrated significant (46%) decline in SUV of metastatic ovarian carcinoma, associated with improved tumor-related symptoms. Nine pts tolerated over 3 cycles and another 4 pts continued treatment over 6 cycles with stable disease. At 105 mg BID, dose- limiting toxicities included nausea, vomiting, diarrhea. Conclusions: At the doses evaluated, PF-00562271 is tolerable with extended BID oral administration and exhibits favorable PK and PD. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented. No significant financial relationships to disclose.

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A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2504 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2504-2504 ◽

Cited By ~ 13

Author(s):

Ravi K. Amaravadi ◽

Neil N. Senzer ◽

Lainie P. Martin ◽

Russell J. Schilder ◽

Patricia LoRusso ◽

...

Keyword(s):

Dose Escalation ◽

Clinical Benefit ◽

Clinical Studies ◽

Drug Exposure ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

Drug Shortage ◽

Apoptotic Pathway ◽

Best Response

2504 Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.

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Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome

Blood Advances ◽

10.1182/bloodadvances.2019000757 ◽

2020 ◽

Vol 4 (9) ◽

pp. 2032-2043 ◽

Cited By ~ 3

Author(s):

Je-Hwan Lee ◽

Stefan Faderl ◽

John M. Pagel ◽

Chul Won Jung ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Phase 1 ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Open Label ◽

Dose Escalation Study ◽

Acute Myeloid

Abstract CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

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3488 A comparison between the Rolling 6 and 3+3 dose escalation study designs for phase 1 clinical trials

Journal of Clinical and Translational Science ◽

10.1017/cts.2019.73 ◽

2019 ◽

Vol 3 (s1) ◽

pp. 30-31

Author(s):

Charles Gene Minard ◽

Rachel Rau ◽

Susan Hilsenbeck ◽

Brenda J. Weigel ◽

Elizabeth Fox ◽

...

Keyword(s):

Study Design ◽

Dose Escalation ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Rank Test ◽

Dose Escalation Study ◽

Signed Rank ◽

Significant Difference ◽

Signed Rank Test ◽

Study Designs

OBJECTIVES/SPECIFIC AIMS: The development of new anti-cancer agents for children requires an inherently longer timeline than in adults. The 3+3 study design for Phase 1 dose escalation trials is commonly used to estimate the maximum tolerated dose and assess safety. The Rolling 6 study design was developed to shorten the study conduct timeline. METHODS/STUDY POPULATION: This study compares twenty Phase 1 COG Pilot and Phase 1 Consortium trials that employed the Rolling 6 design with hypothetical results under the assumption that a 3+3 design had been executed. The number of evaluable patients required to complete the study, number of DLTs, number of inevaluable patients, overall study duration, time suspended to enrollment (i.e., waiting for DLT evaluation), and DLT risk are compared between study designs using Wilcoxon’s signed rank test. RESULTS/ANTICIPATED RESULTS: The Rolling 6 study design required less time to complete the studies compared with 3+3 design (median 273 vs. 297 days, P = 0.01). In general, the Rolling 6 study design required more patients, had more inevaluable patients, and there were more dose limiting toxicity (DLT) events. However, there was no significant difference in DLT risk (median 0.15 vs. 0.17, P = 0.72). DISCUSSION/SIGNIFICANCE OF IMPACT: The Rolling 6 study design effectively shortens the study conduct timeline compared with the traditional 3+3 design for Phase 1 COG Pilot and Phase 1 Consortium trials without increasing the risk of toxicity.

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