Phase I dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as single‑agent and in combination with temozolomide in patients with advanced solid tumors (NCT00920595).

3052 Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in cellular processing of DNA damage via the base excision repair pathway. CEP-9722, an orally available PARP1-2 inhibitor, demonstrated single-agent antitumor activity and synergy with temozolomide (TMZ) in xenograft models. This phase I study evaluated the pharmacokinetics, pharmacodynamics, and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy and combination with TMZ. Methods: Adult patients with advanced solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722 (days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was 150 mg/day in the first cohort and was escalated depending on the occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall, 26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of 3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of CEP-9722 in combination with TMZ (150 mg/m2) was reached at 1000 mg/day. The recommended dose was 750 mg/day. A total of 9 patients were treated at the recommended dose. DLTs were observed in 2 patients during cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000 mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this study, 4 grade 3 treatment-related adverse events were observed. The pharmacokinetics showed high intra- and inter-patient variability at all doses. The pharmacodynamic analysis demonstrated PARP inhibition at all doses, but the high inter- and intra-patient variability prevented any conclusion regarding a dose / PARP inhibition relationship. Conclusions: TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5 and the combination CEP-9722/TMZ was well tolerated. In addition, a clear signal of PARP inhibition was demonstrated.

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A phase I study of bevacizumab (BV) plus ABT-510 in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3541 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3541-3541 ◽

Cited By ~ 1

Author(s):

H. E. Uronis ◽

J. Bendell ◽

G. Blobe ◽

M. Morse ◽

D. Geier ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase Ii ◽

Single Agent ◽

Hematological Toxicity ◽

Synthetic Analog ◽

Advanced Solid Tumors ◽

Increased Risk ◽

Grade 3 ◽

Recommended Phase Ii Dose

3541 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity both alone and in combination. ABT-510 is a 9 amino acid synthetic analog of the N-terminal region of thrombospondin (TSP-1), an endogenous inhibitor of angiogenesis. ABT-510 exhibits anti-angiogenic effects in preclinical models and has been well-tolerated as a single agent in previous Phase I & 2 studies. As a combination anti-angiogenesis therapy, we evaluated BV + ABT-510 in a phase I biomarker study. Methods: In cohorts of 3–6 patients, BV and ABT-510 were evaluated. BV was dosed in mg/kg IV q2weeks and ABT-510 was given daily in mg SC BID; cycle length was 28 days. Dose levels were as follows: (1) BV 5/ ABT-510 50; (2) BV 10/ ABT-510 50; (3) BV 10/ ABT-510 100. At the recommended phase II dose, 20 patients are being enrolled for detailed biomarker studies. DLT was defined as any hematological toxicity = grade 4 or grade = 3 non- hematological event in Cycle 1 related to treatment, with the exception of grade 3 hypertension adequately controlled by medication. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities suggesting increased risk for class-related toxicities. Dermal wound angiogenesis assays were analyzed for visualization as well as phospho-VEGFR2, TGFβ, phospho-AKT, and thrombospondin-1 and -2, both pre- and on-treatment. Plasma was assayed for multiple angiogenic factors. Results: 22 patients have been enrolled; 17 are currently evaluable for toxicity and 14 for efficacy. No DLT were seen in any cohort. Possible treatment related adverse events occurring in later cycles included: gr3 GI bleed (n=1) and gr3 headache (n=1). 7 patients had stable disease as best response (range 8- 64+ weeks); 2 remain on therapy, one at 64+ weeks and one at 24+ weeks. Conclusions: BV + ABT-510 is well-tolerated and has hints of activity in refractory tumors. The recommended phase II dose is BV 10mg/kg IV q14d and ABT-510 100mg SC BID. Updated clinical and biomarker data will be presented. No significant financial relationships to disclose.

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Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3640 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3640-3640

Author(s):

Filip Janku ◽

Elena Elez ◽

Gopa Iyer ◽

Noboru Yamamoto ◽

Daniel Shao-Weng Tan ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Drug Exposure ◽

Mapk Pathway ◽

Single Agent ◽

Human Study ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Grade 3

3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .

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A phase I trial of RAD001 in combination with cetuximab in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14075 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14075-14075 ◽

Cited By ~ 2

Author(s):

A. N. Avadhani ◽

K. Flaherty ◽

M. Rosen ◽

M. L. Veronese ◽

K. Harlacker ◽

...

Keyword(s):

Phase I ◽

Vascular Permeability ◽

Solid Tumors ◽

Metabolic Activity ◽

Mononuclear Cells ◽

Single Agent ◽

Ca 125 ◽

Hematologic Toxicity ◽

Advanced Solid Tumors ◽

Mtor Inhibition

14075 Background: Cetuximab is a selective epidermal growth factor (EGFR) inhibitor approved for use in EGFR expressing advanced colorectal cancers. RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination it may augment anti-tumor activity. We assessed safety, pharmacokinetics (PK), and pharmacodynamic (PD) endpoints for mTOR inhibition and tumor vascular permeability in a phase I combination study. Methods: Pts with EGFR-expressing advanced solid tumors were randomized to a 3 week run-in of single agent RAD001 or cetuximab Q wk, followed by RAD001 + cetuximab Qwk. RAD001 was dosed at 30–70 mg PO. Standard dosing of cetuximab was used (400 mg/m2 IV loading, followed by 250 mg/m2 IV Qwk). DLT was defined as any grade 4 hematologic or =grade 3 non-hematologic toxicity associated with treatment during cycle 1. In addition to plasma analysis for the PK of RAD001, we performed 18FDG-PET and dynamic contrast-enhanced (DCE) MRI before and during combination therapy, to assess for early changes in tumor metabolic activity and vascular permeability. Phosphorylation of p70S6K, a biomarker for RAD001 activity, was measured in peripheral blood mononuclear cells. Results: 12 pts (median age 56, 5 M/7F, median PS 0) were treated at dose levels 1–2 (RAD001 30–50mg/cetuximab 250 mg/m2), with 3 per dose order. Observed toxicities were all grade 1–2, and included mucositis (2/12), rash (8/12), fatigue (6/12), anorexia (4/12), nausea (5/12), and vomiting (5/12). 2 pts (parotid and ovarian CA) had SD (4+ mos) as best response, with decreased serum CA-125 in the ovarian CA pt. PET findings in pts with SD confirm decreased tumor metabolic activity. Conclusions: At these doses, neither drug appears to increase the toxicity of the other. Analysis of full dose RAD001 in the combination is nearing completion. Preliminary PET findings suggest biological activity of the combination. No significant financial relationships to disclose.

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Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies—A California Cancer Consortium NCI/CTEP sponsored trial.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2526 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2526-2526 ◽

Cited By ~ 2

Author(s):

Thehang H. Luu ◽

Paul Henry Frankel ◽

Dean Lim ◽

Mihaela C. Cristea ◽

Jan Hendrik Beumer ◽

...

Keyword(s):

Retinoic Acid ◽

Phase I ◽

Solid Tumors ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Qtc Interval ◽

Advanced Solid Tumors ◽

Eligibility Criteria ◽

Grade 3

2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to <grade 1 within 1 week or non-hematologic toxicity: ≥grade 3. We sought the MTD of belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose levels (DL) were tested starting from belinostat 600 mg/m2/day and 13c-RA 50 mg/m2/day to belinostat 2000 mg/m2/day and 13c-RA 100 mg/m2/day. Only two DLTs were observed: a grade 3 hypersensitivity reaction with dizziness and hypoxia at DL 8 (belinostat 1700 mg/m2/day, 13c-RA 100 mg/m2/day); and a grade 3 allergic reaction in a patient with an ECOG PS 2 at DL 11 (belinostat 2000 mg/m2/day, 13c-RA 100 mg/m2/day). The MTD was not reached. Pharmacokinetics of belinostat suggests dose proportionality. Median number of cycles: 2 (range 1–56). 10 patients had SD including: 1 neuroendocrine pancreatic stable for 56 cycles; 1 breast pt for 12 cycles; 1 lung pt 8 cycles. 2 pt had PRs: a keratinizing squamous cell carcinoma (tonsil) and a lung cancer pt. Conclusions: Belinostat 2000 mg/m2 days 1-5and 13-cis-Retinoic acid 100 mg/m2days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD. Future studies building on this combination to belinostat are warranted. Support: U01CA062505 and P30CA033572 (City of Hope); U01CA099168 and P30CA047904 (University of Pittsburgh).

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Design of a phase I clinical trial with PNT2258, a novel DNA interference oligonucleotide (DNAi), in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps3110 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS3110-TPS3110

Author(s):

Drew Warren Rasco ◽

Anthony W. Tolcher ◽

Amita Patnaik ◽

Kyriakos P. Papadopoulos ◽

Alex Amaya ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Dose Escalation ◽

Mononuclear Cells ◽

Drug Product ◽

Single Agent ◽

Upstream Region ◽

Advanced Solid Tumors ◽

Phase Ii Studies

TPS3110 Background: With the knowledge that Bcl-2 facilitates drug resistance and cell survival, a DNA interference (DNAi) strategy was applied to silence Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic mRNA targeting (antisense, RNAi, and miRNA targets) as it targets genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a novel single-stranded 24-base unmodified DNA designed to bind to an upstream region of the Bcl-2 promoter. The drug product (PNT2258) is PNT100 encapsulated in a specialized pH tunable liposome and is being assessed for safety and tolerability in a phase I trial. PNT2258 avoids the toxicities associated with modified oligonucleotides and double-stranded RNAs; since the liposome formulation is anionic and contains no surface spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated marked single agent activity in a diffuse large cell lymphoma, and therapy potentiation when combined with either rituximab in Daudi-Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An open-label, single-arm, first-in-man phase I dose-escalation study of PNT2258 in patients with advanced solid tumors was designed to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics of PNT2258 to recommend a dose for phase II studies. In this phase I study, pharmacodynamic effects of PNT2258 will be evaluated through analyses of soluble serum and plasma markers and peripheral blood mononuclear cells. Patients will receive PNT2258 as an intravenous infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with PNT2258 administered to one patient per cohort and dose-escalation will proceed by dose-doubling in each successive cohort until a dose level of 64 mg/m2 is attained, provided no dose-limiting toxicities are observed in cycle 1. Thereafter, dose escalations shall proceed at 33% increments of the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions of up to six patients per cohort as needed. The ten planned dose cohorts have been completed with all patients enrolled.

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A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2556 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2556-2556

Author(s):

Igor Puzanov ◽

Patricia LoRusso ◽

Kyriakos P. Papadopoulos ◽

Christopher T. Chen ◽

Yvan LeBruchec ◽

...

Keyword(s):

Antitumor Activity ◽

Solid Tumors ◽

Dose Escalation ◽

Stable Disease ◽

Single Agent ◽

Treatment Withdrawal ◽

Advanced Solid Tumors ◽

Open Label ◽

Phase 1B ◽

Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

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Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.20.3545 ◽

2000 ◽

Vol 18 (20) ◽

pp. 3545-3552 ◽

Cited By ~ 32

Author(s):

Corinne Couteau ◽

Marie-Laure Risse ◽

Michel Ducreux ◽

Florence Lefresne-Soulas ◽

Alessandro Riva ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Solid Tumors ◽

Pharmacokinetic Study ◽

Topoisomerase I ◽

Maximum Tolerated Dose ◽

Hematologic Toxicity ◽

Advanced Solid Tumors ◽

Phase Ii Studies ◽

Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

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