Definition Of Dose-limiting Toxicity Research Articles

First-in-human study of 225actinium mti-201 (225Ac-MTI-201) in metastatic uveal melanoma (UM).

TPS9612 Background: Prognosis in metastatic uveal melanoma (UM) has historically been poor approximating 1 year from diagnosis. Tebentafusp is the only approved systemic agent for HLA-A*02:01 positive metastatic UM, and novel therapies are needed. The melanocortin-1 receptor (MC1R) receptor is highly expressed in UM with limited expression in normal tissues. Actinium-225 (225Ac) is an alpha particle emitting radionuclide ideal for targeted ligand binding due to high linear energy transfer and limited free path (<100 µm) in tissue. We developed a novel MC1R targeted radiopharmaceutical 225Ac-MTI-201, and demonstrated high biostability, affinity, MC1R-specific cytotoxicity with defined dosimetry and pharmacokinetics in pre-clinical studies (1). Murine efficacy studies of UM showed significant delay of tumor growth and improved survival compared to controls. Methods: This is a single institution first-in-human phase I study (NCT05496686) of 225Ac-MTI-201 in metastatic UM. The primary objective is to determine the safety of a single intravenous dose of 225Ac-MTI-201 relative to radioactivity dose. Secondary endpoints include 1) pharmacokinetics (PK) and clearance of 225Ac-MTI-201, 2) objective response rate and duration, progression-free survival, and overall survival in metastatic UM. Salient eligibility criteria include: 1) age ≥18 years; 2) histologically confirmed metastatic UM with progression after at least 1 prior line of therapy; 3) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; 4) Eastern Cooperative Oncology Group performance status of ≤1; 5) adequate marrow, renal and hepatic function; 6) no more than 25% of bone marrow treated with prior radiotherapy. Patients will receive a single dose of 225Ac-MTI-201 under appropriate guidelines and precautions for administration of radiopharmaceuticals. Pre-injection and post-injection PK sampling at defined intervals are undertaken. There are 12 dose levels for 225Ac-MTI-201 being investigated ranging from 4.7 microcurie (µCi) to 1327 µCi. Dose escalation is done using a modified continual re-assessment method with a cohort size of one based on dose limiting toxicity (DLT) assessment within 28 days of drug administration using CTCAE v5.0. Definitions of DLT include G4 neutropenia or febrile neutropenia, G4 thrombocytopenia or G3 thrombocytopenia with clinically significant bleeding, > G3 non-hematological toxicity with selected exceptions, laboratory abnormalities that satisfy Hy’s law, or any death not related to underlying disease or extraneous cause. Response assessments are undertaken with cross-sectional imaging every 8 weeks in year 1, and every 12 weeks in year 2. This study is currently open for enrollment. Dose levels 1-4 have been completed without DLT. 1. Tafreshi, J Nucl Med 2019. Clinical trial information: NCT05496686 .

KB-Lanra 1001: A Phase 1b/2 Study of Safety, PK, PD, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib in Combination with the FLT3 Inhibitor Gilteritinib in FLT3-Mutated R/R AML

Background and Significance: FMS-like tyrosine kinase (FLT3)-mutation (FLT3 mut) in patients with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML) is associated with shorter overall survival (OS) and relapse-free survival. Gilteritinib is an approved therapy for R/R FLT3 mut AML, but reduction in FLT3 mut burden and sustained efficacy are rarely achieved, thus necessitating investigation of rational therapeutic combinations to improve outcomes. Spleen Tyrosine Kinase (SYK) is a non-receptor tyrosine kinase known to regulate intracellular signaling in response to extracellular stimuli via its immunoreceptor tyrosine-based activation motif (ITAM). SYK serves as a relay to an oncogenic transcriptional regulatory network (TRN) linked to HOXA9 and MEIS1-facilitated suppression of myeloid progenitor maturation and proliferation. SYK cooperates with internal tandem duplication (ITD)-mutated FLT3 to drive leukemogenesis. Lanraplenib (LANRA) is an oral, potent, selective, next-generation SYK inhibitor with a 24-hour half-life, and once-daily (QD) dosing. In preclinical studies, the combination of LANRA and the FLT3 inhibitor gilteritinib demonstrated strong antileukemic effects ex vivo, resulting in deeper responses, and extended overall survival in FLT3 ITD-driven AML patient-derived xenograft mouse models. LANRA in combination with gilteritinib is currently being evaluated in patients with R/R FLT3 mut AML in the KB-LANRA 1001 trial (NCT05028751). Study Design and Methods: KB-LANRA 1001 is a global, multicenter, open-label phase 1b/2 trial designed to determine the safety and maximally tolerated and/or recommended phase 2 dose (MTD/RP2D) of LANRA in combination with standard dose gilteritinib (120 mg QD) in patients with R/R FLT3 mut AML. Secondary endpoints include evaluating pharmacokinetics (PK), pharmacodynamics (PD), and response evaluation (complete response (CR), CR with partial hematologic recovery (CRh), duration of response (DoR), event-free survival (EFS) and OS of the combination. Key exploratory endpoints include reduction of FLT3 mutvariant allele frequency among patients who achieve CR/CRh, correlation with selected baseline biomarkers that may predict efficacy outcomes, and assessment of LANRA PD properties (including target engagement). Eligibility requirements include documented FLT3 mut (ITD, tyrosine kinase domain [TKD] or both), age ≥18, and receipt of at least 1 prior therapy. Oral LANRA + gilteritinib will be administered daily until progression/relapse, intolerance, or failure to achieve at least a partial response (PR) after 6 cycles. The phase 1b component will follow a 3+3 dose escalation design. A dose-escalation committee (DEC) will decide LANRA dose escalation based on prospectively defined definitions of dose-limiting toxicity and safety metrics. Enrollment of additional patients to dose cohort(s) previously cleared for safety and tolerability by the DEC will be allowed under specific conditions. The phase 2 component will further evaluate safety, PK, PD, and anti-leukemic activity of the combination at the LANRA RP2D

Utilizing Drug Combo to improve the design of phase 1 trials for anticancer drugs.

1571 Background: Accurate prior knowledge of a single drug or drug combination on toxicity, pharmacokinetics (PK), maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) can help oncologists and statisticians design an efficient phase 1 clinical trial. However, most of the relevant knowledge is shattered in various databases. More importantly, MTD and DLT are missing in any databases. This study constructed a comprehensive knowledge base with expert-curated MTD and DLT knowledge from published anticancer drug combination phase 1 clinical trial results. We also demonstrated the utility of the knowledgebase to design a more efficient phase 1 trial. Methods: Toxicity, pharmacology, and PK knowledge were integrated from publicly available data sources, including DrugBank, SIDER, and drug labels. An interdisciplinary team manually curated the MTD and DLT knowledge. Relevant papers were discovered by PubMed keyword search (drug name + MTD or RP2D). Details regarding patient eligibility, treatment information (dose, formula, and schedule), trial design method, dose levels, DLT definition, MTD or Recommended phase 2 dose, and DLT incident were curated in the structured data format and stored in a database. Rxnorm and MedDRA were used for normalizing drug names and DLT. Results: Currently, 2358 papers on cancer drugs phase 1 trial have been curated. Additionally, pharmacological and PK knowledge of 197 cancer drugs, ADE information from 1094 drug labels, and more than 500000 pieces of DDI evidence were integrated into the knowledge base. This knowledge base (drugcombo.info) could help researchers design an efficient phase 1 trial. For example, based on knowledge from Drug Combo, the combination of nivolumab and axitinib did not have potential PK DDI and severe overlapping toxicity. The reviewing physician considered a phase 1b study to start at a curated 5 mg maximum dose of axitinib with dose reduction to 3 and 2 mg and maintenance of a 3-mg/kg dose of nivolumab based on guidelines. With such additional preliminary knowledge, the reviewing statistician felt the adaptive statistical methods could be applied to redesign this phase I combination trial and minimize patient exposure to sub-therapeutic dose levels. Conclusions: To our knowledge, Drug Combo is the first knowledge that integrated curated MTD and DLT knowledge. It would promote applying curated knowledge to better design phase I trials to treat cancer.

Quasi-partial order continual reassessment method: Applying toxicity scores to cancer dose-finding drug combination trials

The primary endpoint of most dose-finding cancer trials is patient toxicity, and the primary goal is to identify the maximum tolerated dose (MTD), that is, the highest dose that falls below or within a pre-specified toxicity tolerability threshold. Conventionally, dose-finding methods have utilized a binary toxicity endpoint based on whether or not a patient experiences a dose limiting-toxicity (DLT). Improving upon this, in recent years several methods have been developed for modeling toxicity scores, a novel continuous endpoint designed to more precisely estimate patient toxicity burden. Separately, drug-combination trials have become increasingly prevalent, and due to added complexities regarding estimating ‘true’ dose ordering and potential for more complex patient toxicity profiles, provide an ideal setting which may benefit from the improved precision of toxicity scores. In this paper, we merge two frameworks based on the Continual Reassessment Method (CRM) - the Quasi-CRM and the Partial Order CRM (POCRM) – to propose a novel approach for modeling toxicity scores in a combination-trial setting. We demonstrate that utilizing toxicity scores has the potential to greatly improve correct dose-selection over a variety of trial scenarios. We further present a simple adaptation to the toxicity-score model to control for potential over-dosing issues such that it adheres to the conventional DLT definition and will, at worst, perform equivalently to that of the traditional binary DLT framework. We demonstrate that extending toxicity scores to the combination-trial setting offers potential for improvement over the conventional binary endpoint models.

Evaluation of toxicities for intravesical drugs in phase 1 bladder cancer trials.

Improving clinical trial design is important for optimizing approval of safe and effective drugs. Phase 1 clinical trials seek to determine phase 2 doses by investigating predefined dose-limiting toxicities. Traditional definitions of dose-limiting toxicity may not be applicable to intravesical therapies for bladder cancer. This study compared the frequency of dose-limiting toxicities and serious adverse events in bladder cancer trials for intravesical therapies to other routes of administration. Studies were abstracted from ClinicalTrials.gov and reconciled with a PubMed search. Primary and secondary end points were predefined before data abstraction, and the primary end point was subject-level dose-limiting toxicity rate. Fisher exact tests were performed with p<.05 designated as significant. Eighteen intravesical studies and 24 studies with other routes of administration (the per os/intravenous/intramuscular [PO/IV/IM] group) were identified. Dose-limiting toxicities were reported in 38.9% of intravesical studies, affecting 3.29% of subjects, compared with 30.0% of PO/IV/IM studies representing 4.19% of subjects (p=.52 for study-level and p=.60 for subject-level comparisons). Serious adverse events occurred in 53.9% of intravesical studies in 10.3% of subjects versus 91.0% of studies reporting serious adverse events affecting 41.4% of subjects in the PO/IV/IM group (p=.03 for subject-level and p<.0001 for study-level comparisons). There was no difference in subject-level dose-limiting toxicity rate between intravesical and PO/IV/IM bladder cancer trials. The serious adverse event rate was lower in the intravesical group. Heterogeneity of dose-limiting toxicity definition may affect interpretation of toxicity in phase 1 bladder cancer clinical trials studying different routes of administration. Bladder cancer is a common cancer type that may be treated with therapies that are instilled into the bladder and act locally, called intravesical therapies. This study used publicly available regulatory data from early phase clinical trials to determine whether measures of tolerability used in clinical trials are applicable to intravesical therapies for bladder cancer.

Phase I/IB Study of Azacitidine and Hedgehog Pathway Inhibition with Sonidegib (LDE225) in Myeloid Malignancies

Background: Lower intensity therapies for patients (pts) with myeloid malignancies (AML, MDS, CMML, MPNs) are beneficial, but suboptimal despite the emergence of potentially active new agents. Even after an initial response to hypomethylating agents (HMAs) [5-Azacitidine (AZA) or decitabine], the majority of patients fail treatment. In large-scale RNAi screens we identified Hedgehog pathway (HP) genes as a potential rational combination to overcome a priori and acquired HMA resistance. Herein we report the first analysis of the final study results of the oral smoothened (SMO) inhibitor, Sonidegib (LDE225) in combination with AZA in 63 pts treated on a Phase 1/1B (Ph1/1B) trial.Methods: Ph1 (3+3) dose escalation and Ph1B (expansion cohort) study to determine the MTD (Ph1) and best overall response (Ph1B) of Sonidegib (SON) combined with AZA. 2nd endpoints included AEs, DOR, TTP, OS, time to AML for MDS pts and QOL. Pts with untreated and relapsed/refractory (rel/ref) AML, CMML, MDS, MDS/MPN overlap (MDS/MPN) or myelofibrosis (MF) were eligible. SON was started at dose level (DL) 0 at 400mg oral daily continuously (28 day cycle) and AZA at 75mg/m2 x 7 days or days 5-2-2 with dose adjustment per label. Dose-limiting toxicity (DLT) in Ph1 was assessed after 42 days at steady-state concentrations of SON. Pharmacokinetics were not performed.Results:Study population:From 05/2014 to 05/2017 (data cut-off) 63 pts were enrolled and followed for outcome: 10 pts were treated on the Ph1 and 52 in Ph1B part of the trial (1 pt withdrew). Median age was 72.5 years (range 39-86) and 66% pts were male. ECOG 0, 1 and 2 are 34%, 61% and 5% respectively. 45% (n=28) were newly diagnosed and 55% (n=34) rel/ref pts. 38 pts (61%) had AML and 13 of the 15 newly diagnosed/untreated AML pts had 2nd AML due to AHD; 23/38 pts had rel/ref AML. For all AML pts 21/38 were intermediate risk and 16/38 had unfavorable cytogenetics (1/38 unknown). 18 pts (29%) had MDS, all in the Intermediate, High or Very High risk status (IPSS-R), 4 (6.5%) had CMML and 2 pts MF.Dose levels, treatment administration and follow up: 6 pts were treated at DL0 SON 400mg/day continuously with AZA and 1 DLT of CPK elevation observed, while another pt had grade 4 neutropenia (at that time included in DLT definition, later removed). Due to overall tolerance of the combination at DL0 and investigator assessment, despite only 1/6 formal DLTs, DL -1 at SON 200mg x28 days was explored without further DLT (n=4 pts) and 52 pts accrued on Ph1B. For the 56 pts treated at the MTD dose of SON 200mg (Ph1B=52 and Ph1=4 pts), after a median of 14.5 months follow up, 218 cycles have been administered (median 3 cycles-range 1-25 ms). Median doses for SON and AZA were 200mg and 75mg/m2 respectively. 12.5% and 18% of pts had dose adjustments and 71.4% (i.e. missed only 1 dose) and 18% dose omissions at least once for SON and AZA respectively. 19/56 (34%) of pts are alive.Safety and Tolerability : Of 56 pts treated at MTD dose100% experienced at least one grade (gr) 3 AE and 52 (93%) had a gr 4 AE regardless of attribution. 96% and 91% had a gr 3 and gr 4 Heme AE and 73% and 20% had a gr 3 and gr 4 Non-Hem AE respectively. Gr 3/4 AEs were as expected for either drug and the diseases under study and were: thrombocytopenia (n=51), neutropenia (47), anemia (43), leukopenia (41). Most common gr 1/2 AEs were: fatigue (n=48), constipation (29), nausea/cough (each 24), insomnia (19), diarrhea (18), abdominal pain (16). 4/56 pts died on study deemed not drug related (cardiac arrest, MOF, neoplasm, sudden death).Efficacy: With a median follow up of 14.5 ms the best response outcome for untreated AML/MDS patients was 23.1% and for rel/ref 7.1%. However, the rate of SD (NR) was remarkably high particularly in the rel/ref AML population at 76% (16/21 pts, 2 not yet assessed). This high disease control rate was reflected in an OS of 7.6 ms (4.6-NE) in rel/ref AML, the majority of which failed previous HMAs .Conclusion: In this, to date largest SMO inhibitor/HMA combination trial, the oral SMO inhibitor SON was safe with full dose AZA in untreated and previously treated AML, MDS/CMML and MF pts. Although remission rates are not superior to single agent AZA in the heavily pre-treated and advanced myeloid malignancy population, the OS and lack of progression are encouraging, particular in the rel/ ref AML population indicating that SMO/Hh pathway inhibition may add to HMA efficacy. Predictive biomarker studies are ongoing. DisclosuresMesa:Ariad: Consultancy; Galena Biopharma, Inc.: Consultancy; CTI BioPharma Corp.: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Promedico: Research Funding; Gilead Sciences, Inc.: Research Funding; Celgene Corporation: Research Funding.

Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases

Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases. To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other. This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non-small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019. The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP). The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated. A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non-small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients. This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute-sponsored trials (NRG-BR002, NRG-LU002). ClinicalTrials.gov Identifier: NCT02206334.

A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors.

10527 Background: Proangiogenic signaling pathways cooperate with mTOR-mediated regulation of cell growth and maintenance to drive development of many pediatric cancers. We report results of the phase 1 dose escalation for LEN + EVE in pediatric patients (pts) with recurrent solid and CNS tumors conducted by Children’s Oncology Group. Methods: Dose escalation was conducted using a rolling-6 design. Pts received LEN + EVE orally once daily in continuous 28-day cycles. Dose determination was based on toxicity (CTCAE v4.03) during cycle 1. Pharmacokinetics (PK) of plasma LEN and EVE were monitored. Results: 17 pts were enrolled (9 male; 8 female). Median (range) age was 10 (3–21) years; 8 pts had CNS tumors. 17 were evaluable for dose-limiting toxicity (DLT). Enrollment started at dose level 1 (DL 1; LEN 11 mg/m2 + EVE 3 mg/m2) and, after treatment of 3 pts, was initially de-escalated to DL –1 (LEN 8 mg/m2 + EVE 3 mg/m2) due to DLT of proteinuria in 1 pt and self-resolving headache in another who, on review, did not meet the definition of DLT. No pts enrolled at DL –1 (n = 5) experienced DLT. Overall, DLTs were observed in 2 of the first 6 patients enrolled at DL 1: the initial pt with proteinuria and 1 more pt with hypertriglyceridemia and hypercholesteremia. Because 2 pts had reversible DLT of different categories not related to Cmax or AUC, the DL 1 cohort was expanded to enroll an additional 6 pts, none of whom had DLT. Thus, 2/12 pts experienced DLT at DL 1. Overall, most common treatment-emergent adverse events (TEAEs; ≥ 50% of pts) were diarrhea, hypertension, hypertriglyceridemia, vomiting, abdominal pain, headache, and hypothyroidism. 47% of pts had ≥ 1 treatment-related TEAE grade ≥ 3; the most frequent was proteinuria (n = 2). On cycle 1 day 15, mean (SD) Cmax (ng/mL) for LEN at DL –1 and DL 1, respectively, was 314 (150) and 359 (270), and mean (SD) AUC0-8h (hr•ng/mL) for LEN was 1570 (935) and 1780 (1100). Taking all toxicities and PK into account, no further dose escalation was recommended. Best overall response in pts with measurable disease was 2/11 stable disease, 7/11 progressive disease, and 2/11 not evaluable. Conclusions: The recommended phase 2 dose of LEN + EVE in children with solid and CNS tumors was LEN 11 mg/m2 + EVE 3 mg/m2, with maximum daily doses capped at 18 mg and 5 mg, respectively. The toxicity profile was no more than additive to single-agent therapy. PK exposure was comparable with children on single-agent LEN and to adults receiving LEN + EVE. Enrollment to the phase 2 portion (Ewing sarcoma, high-grade glioma, and rhabdomyosarcoma strata) is ongoing. Clinical trial information: NCT03245151.

Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib

BackgroundPoly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited.MethodsOlaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses.DiscussionWe designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity.Trial registrationClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).

Abstract P2-09-15: A phase I study of interferon-gamma (γ)plus weekly paclitaxel, trastuzumab and pertuzumab in patients with HER-2 positive breast cancer

Abstract Background: IFN-γ, a cytokine that plays diverse roles in innate and adaptive immunity, has been shown to be essential in anti-tumor immune response. In vitro and in vivo studies have shown the synergistic effect of IFN-γ in combination with HER2-targeting monoclonal antibodies with or without taxane chemotherapy. We have conducted a phase 1 clinical trial of systemic IFN-γ in combination with trastuzumab, pertuzumab, and paclitaxel in HER2-positive metastatic breast cancer. Methods: Two dose levels (DL) of IFN-γ, 50 (DL1) and 75 mcg/m2 (DL2), were evaluated. IFN-γ was given as subcutaneous injection three times weekly starting on day 1 of therapy for 12 weeks. Paclitaxel was administered intravenously (IV) weekly at 80mg/m2 in combination with trastuzumab IV (8 mg/kg loading dose, then 6 mg/m2 q 21 days) and pertuzumab IV (840 mg loading dose, then 420 mg q 21 days). Eligible patients had measurable metastatic HER2-positive breast cancer, were candidates to receive paclitaxel chemotherapy, and had an ECOG PS 0-1. The primary objective of this study was to evaluate the safety and tolerability of the combination therapy during the 12 weeks of treatment and to determine the recommended phase II dose (RP2D). Dose-limiting toxicity (DLT) during cycle one was defined as follows: Non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy which lead to chemotherapy treatment delays &amp;gt; 14 days. Results: A total of nine patients (3 on DL1 and 6 on DL2) were enrolled between 2/2017 and 11/2017. No DLT was observed. For DL1, no serious adverse events (SAE) or significant adverse events (AE) were observed among 3 patients who completed 12 weeks of treatment. For DL2, two out of 6 patients had SAEs including grade 3 pneumonitis (at week 8; treatment was subsequently discontinued) and grade 3 non-neutropenic fever (at week 6), which were possibly related to study treatment. These toxicities, however, did not meet the protocol definition of DLT. Based on these findings suggesting an improved tolerability of DL1 (50 mcg/m2), DL1 was selected as the RP2D. The most frequently observed grade 1 and 2 AEs that were at least possibly related to IFN-γ were fatigue (45%) nausea (36%), myalgia (36%), and fever (27%) diarrhea (18%). No grade 4 AE was noted. Grade 3 AEs included diarrhea, nausea, pneumonitis, non-neutropenic fever. Three out of 9 patients achieved partial response and 6 patients had stable disease per RECIST criteria. Conclusion: IFN-γ in combination with trastuzumab, pertuzumab, and paclitaxel was well tolerated in patients with HER2-positive metastatic breast cancer. Updated results will be presented and the phase 2 neoadjuvant trial is ongoing to further assess the efficacy of this approach. Citation Format: Han HS, Khong H, Costa R, Loftus L, Goodridge D, Henry T, Soliman H, Ismail-Khan R, Fridley B, Czerniecki B. A phase I study of interferon-gamma (γ)plus weekly paclitaxel, trastuzumab and pertuzumab in patients with HER-2 positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-15.

Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer

There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMBtrial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100mg 3-weekly, starting 2weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMBtrial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.

A Phase I Trial of the PI3K Inhibitor Buparlisib Combined With Capecitabine in Patients With Metastatic Breast Cancer

BackgroundBuparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer. Patients and MethodsPatients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m2) for 2 weeks with a 1-week break. Dose escalation used a traditional “3 + 3” design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose. ResultsOf the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m2 twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted. ConclusionThe combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug–drug interactions and more accurate predictive biomarkers of response.

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium

BackgroundDose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. MethodsThe Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. ResultsThirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III–IV haematologic toxicities that were transient or asymptomatic and grade III–IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. ConclusionDLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials.

Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study

IntroductionCrotoxin has a broad antitumor activity but has shown frequent neurotoxic toxicity. To induce tolerance and limit this toxicity, we propose a new design with intra-patient dose escalation.MethodsA new Dose Limiting Toxicity definition was used. The concept of Target Ceiling Dose was introduced.ResultsDose Limiting Toxicity was the inability to dose escalate twice. Target Ceiling Dose was the highest planned dose to be administered to a patient and could change for patients along time. Recommended Dose was defined similarly as in a (3 + 3) conventional design.ConclusionThis innovant design was used and the clinical trial is now closed for inclusions. Results will be presented later.

Patient-reported tolerability of adverse events in phase 1 trials

BackgroundPhase I experts recommend revisiting dose-limiting toxicity (DLT) definition to include chronic and cumulative toxicities induced by new molecularly targeted therapies. Patient’s assessment of late toxicities’ tolerability is, however, unknown.Materials and methodsA prospective survey on adverse events (AEs) tolerability on 23 National Cancer InstituteCommon Terminology Criteria for Adverse Event, Version 4 (NCI-CTCAE.v4) items was conducted at Gustave Roussy’s Phase I department. Patients’ maximum tolerability duration was recorded at baseline, during trial and at trial completion. Results were compared with the corresponding physicians’ survey.Results52 patients enrolled in 27 Phase I trials between May 2014 and November 2015 completed 102 forms. At baseline, the most feared G2/G3 AEs were haematuria (74%), vomiting (71%) and hyperglycemia (64%)/dry mouth (94%), hyperglycemia (92%) and vomiting (92%). At trial completion, the most feared G2/G3 AEs were personality change (83.3%), haematuria (82%) and fever (80%)/dry mouth, fever and dizziness (100% each). Tolerability score did not differ over time. More previous treatments and occurrence of severe AEs were associated with better tolerability at study completion (p=0.0234 and p=0.0153, respectively, in multivariate analysis). Patient’s tolerability differed from physician’s assessment.ConclusionAEs considered intolerable by patients are toxicities that directly impact their quality of life and differ from those feared by physicians or included in DLT definition. Patient-reported tolerability of AEs may help in optimising drug development.

Phase 1 Results of FF-10501-01, a Novel Inosine 5'-Monophosphate Dehydrogenase Inhibitor, in Advanced Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), Including Hypomethylating Agent (HMA) Failures

Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in a Phase 1 clinical study in advanced AML and MDS, including HMA failures.Previous preclinical studies demonstrated potent anti-proliferative and apoptotic effects of FF-10501-01 on AML cell lines, including HMA-resistant derivatives, through inhibition of de novo guanine nucleotide synthesis. Therefore, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ≥ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. A total of 29 patients, 15M and 14F (23 AML, 6 MDS) have been treated in 7 dose cohorts (50 - 500 mg/m2 PO BID) for 14 days on and 14 days off, and 400 mg/m2 for 21 days on and 7 days off, each 28-day cycle. Median (range) values: age 75 yrs (59 - 88); baseline bone marrow blast counts for AML 34% (12 - 82), for MDS 10% (5 - 16), and overall 30% (5 - 82); and prior treatment regimens 2 (1 - 7). All patients relapsed from, or progressed on, prior HMAs.At baseline, mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A, NOTCH1, JAK2, IDH2, PTPN11, KRA, TP53, RUNX1, EZH2 and/or MDM2 were present in 13 of 29 (45%) of patients.Atrial fibrillation (Gr 2) was reported in 2 subjects at a dose of 500 mg/m2 BID. This met the definition of dose-limiting toxicity (DLT) and no further enrollment was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose level lower, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. FF-10501-01 has been very well tolerated through 24 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related thrombocytopenia, neutropenia and bone marrow aplasia (all Gr 4) were reported in 1 patient at 200 mg/m2 BID.The median number of FF-10501-01 cycles received to date is 2 (range 1 - 24). Partial remissions have occurred in 2 AML patients (50 and 100 mg/m2 BID) after 3 cycles, lasting for 5 and 24 cycles, respectively, with the higher dose patient still on study after 24 cycles. A total of 8/23 (34.8%) AML patients, including the 2 PRs, have attained stable disease (SD) control with no disease progression over 3 - 24 cycles. Three AML patients remain on study through 3, 23 and 24 cycles, respectively.A bone marrow complete response was achieved in 1 MDS patient treated at 400 mg/m2 BID after 1 cycle. Although the bone marrow blast counts have increased since, this patient remains stable and is still on therapy through 14 cycles. Three of 6 MDS patients (50%), including the marrow CR, attained SD control with no disease progression over 3, 14 and 14 cycles, and 2 remain on study through 3 and 14 cycles, respectively.FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t1/2 of 4.05 hours. Drug exposure (AUC0-24 and AUCcourse) increased with dose in a near linear manner.Potent suppression of circulating xanthine monophosphate (XMP), a marker of IMPDH activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 and 2 at dose levels of 50 mg/m2 BID and above.FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS in patients who have failed or progressed on HMAs and with one or more baseline mutations in pathways known to be affected in AML and MDS. Preclinical activity was seen in multiple leukemia cell lines, including HMA-resistant derivatives. In a Phase 1 trial, clinical activity with a marrow CR, PRs, long-term disease stabilization (≥ 5 cycles) and a highly tolerable safety profile were observed. The Phase 2a expansion phase of the study is soon to begin. DisclosuresDiNardo:Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Denton:Westat Corporation: Employment. Smith:Westat Corporation: Employment. Tiefenwerth:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

Dose-Seeking Phase I Trials for Currently Approved Molecular-Targeted Therapies in the USA: The Dose-Limiting Toxicity Definition Issue

Background There is substantial evidence that classically used toxicity-driven dose-escalating phase I trials are not optimal for defining the recommended phase II dose for molecular-targeted therapies.

Phase I Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

Phase I Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

Abstract PR13: Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions

Abstract Background: Gene fusions involving the NTRK1, 2 and 3 genes result in constitutively-active TRKA, -B, and -C kinases that are prevalent in a wide array of tumor types, including lung adenocarcinoma, thyroid, head and neck cancer, sarcoma, and other tumors. LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective inhibitor of TRKA, TRKB, and TRKC being studied in a Phase 1 dose escalation trial. In pre-clinical in vivo xenograft mouse models bearing NTRK-fusions LOXO-101 demonstrated potent tumor growth inhibition and regression. Here, we report updated PK and safety data on 24 patients (pts). Methods: In this on-going open-label, multicenter, 3+3 dose escalation Phase I study of LOXO-101, 24 pts with solid tumors refractory to standard therapy, normal hematopoietic and major organ function have been enrolled. LOXO-101 is administered orally as a single dose, followed by QD or BID doses for continuous 28-day cycles. Response is measured by RECIST Criteria, version 1.1. Serum is collected for pharmacokinetic analysis on Cycle 1 Day 1 and Day 8. Safety information is collected on all patients and the definition of dose-limiting toxicity applies to adverse events regardless of relationship to investigational product. Nude mice were injected with CUTO3.29 (MPRIP-NTRK1, lung adenocarcinoma) or MO-91 (ETV6-NTRK3, acute myeloid leukemia) cell lines and then administered LOXO-101 orally at 60 or 200mg/kg daily for 2 weeks. Results: As of September 3, 2015, 24 pts have been treated at each of the first five dose levels (50mg QD, 100mg QD, 200mg QD, 100mg BID, and 150mg BID). LOXO-101 has been well tolerated; the MTD has not been reached and the most common adverse events are Grade 1 and 2 fatigue (42%), dizziness (29%) and anemia (21%). Two pts have had grade 3 AEs leading to dose cohort expansions: elevated AST, grade 3 (Dose Level 150mg BID) and delirium, grade 3 (Dose Level 100mg BID). Each case was subsequently deemed unrelated to study drug by the treating investigator, and the pts remained on study at reduced doses without recurrence. PK analysis showed maximum plasma concentrations of LOXO-101 were reached 30-60 minutes following dosing. The unbound drug levels of LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at peak concentrations at all dose levels. All three pts with NTRK-fusions enrolled have achieved a PR: an undifferentiated sarcoma with an LMNA-NTRK1 fusion (59% decrease; 7 cycles+), a c-kit-negative GI Stromal Tumor (GIST) with an ETV6-NTRK3 fusion (30% decrease; 2 cycles+), and a mammary analogue secretory carcinoma of the salivary glands with an ETV6-NTRK3 fusion (64% decrease; 2 cycles+). These patients were treated at either 100 or 150 mg BID. These data are supported by in vivo tumor regression in xenograft mouse models of NTRK1 and NTRK3 fusion bearing tumor cells of different histologies in the presence of clinically achievable concentrations of LOXO-101. Conclusions: LOXO-101 has been well tolerated and has sufficient systemic exposure for robust tumor responses in 3 of 3 (100%) of NTRK-fusion pts enrolled on study. These data further validate this molecular target as an oncogenic driver across diverse tumor histologies and support the exploration of TRK inhibition in cancer pts with NTRK-fusions. Citation Format: David S. Hong, Marcia S. Brose, Robert C. Doebele, Alice T. Shaw, Afshin Dowlati, Todd M. Bauer, Anna F. Farago, Adriana Estrada-Bernal, Anh T. Lee, Michael C. Cox, Nisha Nanda, Jennifer A. Low, Howard A. Burris, III. Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR13.

Statistical controversies in clinical research: requiem for the 3 + 3 design for phase I trials

More than 95% of published phase I trials have used the 3 + 3 design to identify the dose to be recommended for phase II trials. However, the statistical community agrees on the limitations of the 3 + 3 design compared with model-based approaches. Moreover, the mechanisms of action of targeted agents strongly challenge the hypothesis that the maximum tolerated dose constitutes the optimal dose, and more outcomes including clinical and biological activity increasingly need to be taken into account to identify the optimal dose. We review key elements from clinical publications and from the statistical literature to show that the 3 + 3 design lacks the necessary flexibility to address the challenges of targeted agents. The design issues raised by expansion cohorts, new definitions of dose-limiting toxicity and trials of combinations are not easily addressed by the 3 + 3 design or its extensions. Alternative statistical proposals have been developed to make a better use of the complex data generated by phase I trials. Their applications require a close collaboration between all actors of early phase clinical trials.