Phase I study of everolimus in combination with fluvastatin and zoledronic acid in patients with solid tumours.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13585-e13585
Author(s):  
Charlotte Rose Lemech ◽  
Antoinette Fontela ◽  
Hendrik-Tobias Arkenau ◽  
Melvin T.M. Chin ◽  
Sandra Li ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Phase I ◽  
Phase 1 ◽  
Median Number ◽  
Solid Tumours ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Open Label ◽  
Post Dose ◽  
Best Response

e13585 Background: Everolimus (E) is an mTOR inhibitor with broad anti-tumour clinical activity. There is preclinical evidence of synergistic activity through the combination of E with fluvastatin (F) and zoledronic acid (ZA). F, an HMG CoA reductase inhibitor, and ZA, a bisphosphonate, have both been shown preclinically to inhibit isoprenylation (addition of hydrophobic molecules) of key signalling proteins with subsequent inhibition of the Ras pathway. We investigate their potential activity further in this open-label phase I trial. Methods: Patients (pts) with advanced solid tumours were treated with escalating doses of E, F and ZA to evaluate safety, clinical activity, pharmacokinetics (PK), pharmacodynamics (PD) and the recommended dose for further study. PK samples were obtained over 24 hrs on day 1 and 8 of cycle 1 and day 1 of cycle 2. Pre- and post-dose PBMCs were analysed for markers of MAPK and PI3K-AKT-mTOR pathways (pERK, pAKT and pS6). Results: Maximum doses of each drug in combination (DL 4) were feasible and no DLTs were observed. Of the 16 pts evaluable [median age=63yrs (range 47-81)], the median number of cycles was 3.8 (range 1-8), with 44% of pts receiving ≥ 4 cycles. Drug related toxicities were mainly G1/2, many within the expected toxicity profile of E, including fatigue (12 pts, 75%), myalgias (9 pts, 56%), anorexia (8 pts, 50%), infection (8pts, 50%), dyspnoea (7pts, 44%), diarrhoea (7 pts, 44%), nausea (7 pts, 44%), peripheral oedema (5 pts, 31%) and mucositis (4 pts, 25%). G3 adverse events were predominantly due to symptoms of disease progression. G1/2 anemia and thrombocytopaenia were the most common haematological toxicities, particularly in DL 3 and 4. 44% of pts achieved stable disease as best response (mean 4.5m [range 3-6m]); including 2 CRC pts (DL 4) and 2 CRPC pts (DL 3 and 4). PK and PD results will be presented in further detail. Conclusions: The combination of E/F/ZA is feasible without any added or overlapping toxicities in this phase 1 study. [Table: see text]

Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7556-7556
Author(s):  
Hun Ju Lee ◽  
Michael Y. Choi ◽  
Tanya Siddiqi ◽  
Jacqueline Claudia Barrientos ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
Best Response ◽  
Car T ◽  
Treatment Naïve

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant solid tumors: Safety and efficacy as single agent.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16643-e16643
Author(s):  
Robin Lewis Jones ◽  
Teresa Macarulla ◽  
John A. Charlson ◽  
Brian Andrew Van Tine ◽  
Lipika Goyal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Clinical Activity ◽  
Tumor Type ◽  
Dna Hypermethylation ◽  
Efficacy Evaluation ◽  
Open Label ◽  
Isocitrate Dehydrogenase 1

e16643 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) & unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] & withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in > 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]

Sunitinib for patients (pts) with advanced imatinib (IM)-refractory GIST: Early results from a “treatment-use” trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9540-9540 ◽  
Author(s):  
J. A. Morgan ◽  
C. R. Garrett ◽  
H. J. Schutte ◽  
H. Hurwitz ◽  
L. S. Rosen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Median Number ◽  
Clinical Activity ◽  
Open Label ◽  
Efficacy Data ◽  
Clinical Endpoints ◽  
Early Results ◽  
Best Response ◽  
Hand Foot Syndrome ◽  
Treatment Use

9540 Background: Pts with advanced or metastatic GIST are typically treated first with IM, but many GISTs develop resistance to IM over time or are initially resistant this agent, and a small fraction of GIST pts are intolerant of IM therapy. Sunitinib malate (previously known as SU11248) is an oral, multitargeted tyrosine kinase inhibitor of KIT, PDGFR, VEGFR, FLT3, and RET that has demonstrated efficacy in extensive prior trials involving IM-refractory GIST pts. Since GIST pts who were ineligible for participation in sunitinib clinical trials might derive significant benefit from this therapy, a treatment-use program was implemented for this purpose. Methods: This on-going, multicenter, open-label trial was designed to grant access to sunitinib for treatment use in pts who were ineligible for other sunitinib trials and who had advanced IM-resistant GIST or documented intolerance to IM. Pts on sunitinib are monitored closely to assess clinical benefit as judged by the investigator. Sunitinib is administered at a starting dose of 50 mg/day on a 4/2 schedule (4 consecutive weeks on, 2 weeks off treatment). Clinical endpoints include safety and tolerability, as well as disease control (TTP), response rates, and survival. Results: Of 268 GIST pts enrolled in this treatment-use trial at the time of this analysis, 247 had received at least one dose of sunitinib. The median number of cycles completed was 2 (range, 0–9), and the median number of days on treatment was 83 (range, 1–385). The most frequently reported treatment-related AEs were fatigue (36%), diarrhea (31%), nausea (27%), and hand-foot syndrome (15%), which were generally grade 1/2. At the time of analysis, preliminary efficacy data were available for 152 pts. Of these, 123 pts remain on therapy and have received a median of 3 (range, 2–7) cycles of sunitinib. Based on initial investigator assessments, one pt achieved a CR, 14% achieved PR and 63% have noted SD as best response. Conclusions: Sunitinib was associated with acceptable tolerability in this population of IM-refractory GIST pts enrolled in this treatment-use trial. Consistent with previous results, promising clinical activity was seen, and expanded tolerability and efficacy data will be presented. [Table: see text]

Phase I Study of AVE1642 Anti IGF-1R Monoclonal Antibody in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1166-1166 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Hulin ◽  
Thierry Facon ◽  
Mario Boccadoro ◽  
Dominique Mery-Mignard ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Phase I Study ◽  
Clinical Activity ◽  
Diabetic Patients ◽  
Human Antibody ◽  
Synergistic Activity ◽  
Open Label

Abstract Rationale: CD221 (IGF-1R) is aberrantly expressed in multiple myeloma (MM) and is associated with disease severity (Bataille et al, Haematologica2005;90:706). IGF-1R is thus an attractive therapeutic target in patients with advanced disease. Patients and methods: We have conducted an open-label dose escalation phase I study of AVE1642, anti IGF-1R monoclonal antibody, in patients with advanced MM. The primary objective was to determine the selected dose of AVE1642 administered every 3 weeks (q3w) based on pharmacokinetic (PK), pharmacodynamic (PD) parameters and dose limiting toxicities. The secondary objectives were to assess the safety profile, the biological activity (saturation of receptors) on peripheral granulocytes, the potential immunogenicity and preliminary clinical activity of AVE1642. Results: 14 patients have been treated with AVE1642 as IV infusion administered q3w (day 1 = day 22) at 3 different dose levels: 3 (n = 4), 6 (n = 6) and 12 mg/kg (n = 4). A median number of 2 infusions (1–8) were administered. AVE1642 was well tolerated, except reversible grade 3 hyperglycemia observed in 2 diabetic patients. No hypersensitivity during infusion was reported. No human antibody anti AVE1642 was detected. One patient with Bence-Jones MM experienced a decrease in proteinuria and relief of bone pain. Based on PK/PD results, the dose of 12 mg/kg of AVE1642 has been selected for further clinical evaluation in MM patients. Based on the in vitro synergistic activity of AVE1642 + bortezomib (Descamps et al, ASH2006, 845a), we have started a combination trial of AVE1642, 12 mg/kg q3w + bortezomib (1.3 mg/m2 at d1, d4, d8 and d11 q3w) in patients with advanced MM.

scholarly journals A Dose-Escalation (DE) Study with Expansion Evaluating Safety, Pharmacokinetics and Efficacy of the Novel, Balanced PI3K/mTOR Inhibitor PQR309 in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5893-5893 ◽  
Author(s):  
Graham P. Collins ◽  
Rakesh Popat ◽  
Anastasios Stathis ◽  
Fatime Krasniqi ◽  
Toby A. Eyre ◽  
...  
Keyword(s):  
Phase 1 ◽  
Solid Tumours ◽  
Dose Finding ◽  
Clinical Activity ◽  
Open Label ◽  
Mtor Inhibition ◽  
Dosing Schedule ◽  
Systemic Treatments ◽  
Refractory Lymphoma

Abstract Background:PQR309 is an oral balanced, pan-PI3K, mTORC1 and mTORC2 inhibitor. It is in clinical development for the treatment of solid tumors and hematologic malignancies. 1st generation mTOR inhibitors inhibit the activity of mTOR within the TORC1 complex only with activation of TORC2 proposed as a putative resistance mechanism. PI3 kinase inhibition may reduce subsequent AKT activation which can bypass some effects of mTOR inhibition. Potent antiproliferative activity of PQR309 was previously demonstrated in lymphoma cell lines in vitro and in vivo. Maximum tolerated dose (MTD) of PQR309 in solid tumours was established at 80 mg using a continuous once daily dosing schedule (OD). Methods:We performeda modified 3+3 DE of PQR309, open label phase 1 trial with expansion, to evaluate safety, pharmacokinetics (PK) and efficacy. Patients with relapsed or refractory lymphoma (any sub-type, ECOG PS of 0-1) were treated in two sequential cohorts with escalating doses of PQR309 administered on an OD dosing schedule to assess the MTD of PQR309. The starting dose of PQR309 was 60mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). PK samples were obtained at predefined time points. Clinical efficacy was evaluated according to revised Cheson criteria. In the expansion phase, patients will be treated at the MTD as defined in the DE phase of the study. Results: 15 patients were enrolled between August 2015 and March 2016 and treated with 60mg (n=8) or 80mg (n=7) of PQR309. Demographics: 5F:10M; median age 60 (range: 34-75), median number of prior systemic treatments 5 (range: 1-8). Lymphoma indications are shown in Table 1. Mean duration on therapy was 39 days (range: 3-160). One patient with follicular lymphoma remains on treatment. Grade (G)3/4 drug-related AE were seen in 3 patients treated with 60mg: 1 G4 rhabdomyolysis, 1 G4 neutropenia, 1 G3 hyperglycemia and one patient who developed G3 anorexia and G4 sepsis. Four patients treated with 80mg developed G3/4 drug-related AEs: two patients developed G3 hyperglycemia, one patient developed G3 fatigue and G3 pneumonitis. No DLT was observed. Preliminary PK showed rapid absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 50 hours, consistent with PQR309 studies in solid tumours that evaluated dose levels from 10 to 150 mg PQR309. Responses observed in each patient are shown in the table below. 4 patients were non-evaluable, 3 due to disease progression requiring cessation of study drug and one requiring steroid doses exceeding protocol defined criteria, all within the 21 day DLT assessment period. Conclusion:The MTD and recommended PQR309 dose for the expansion of the study was 80mg OD, in agreement with earlier dose-finding studies in solid tumours. Adverse event patterns were consistent with those seen in studies involing solid tumours. Hyperglycemia, a predicted on-target effect of PI3K/mTOR inhibition, was observed in the majority of patients, providing evidence of pharmacodynamic effects of PQR309. PK was dose-proportional. Encouraging clinical activity including a CR was observed. The study expansion is ongoing. Disclosures Collins: Takeda: Consultancy, Honoraria, Speakers Bureau. Eyre:GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Ivanova:PIQUR: Employment. Schmitz:PIQUR: Employment. Dimitrijevic:PIQUR: Employment. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types

BMJ Open ◽  
2017 ◽  
Vol 7 (11) ◽  
pp. e017075 ◽  
Author(s):  
Caroline Lonez ◽  
Bikash Verma ◽  
Alain Hendlisz ◽  
Philippe Aftimos ◽  
Ahmad Awada ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Antitumour Activity ◽  
Tumour Cells ◽  
Solid Tumours ◽  
Metastatic Tumour ◽  
Clinical Activity ◽  
Open Label ◽  
Open Label Phase

IntroductionNKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning.Methods and analysisThis open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×108, 1×109 and 3×109NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours.Ethics approval and disseminationEthical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals.Trial registration numberNCT03018405, EudraCT 2016-003312-12; Pre-result.

A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3023-3023 ◽  
Author(s):  
Carlos Becerra ◽  
Jeffrey R. Infante ◽  
Lawrence E. Garbo ◽  
Michael S. Gordon ◽  
David A. Smith ◽  
...  
Keyword(s):  
Growth Factors ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Post Dose

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.

scholarly journals 515 A phase 1 study of myeloid modulating agent MTL-CEBPA in combination with pembrolizumab in adult patients with advanced solid tumours

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A545-A545
Author(s):  
Ruth Plummer ◽  
Mikael Sodergren ◽  
David Pinato ◽  
Debashis Sarker ◽  
Vikash Reebye ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Myeloid Cell ◽  
Maximum Tolerated Dose ◽  
Solid Tumours ◽  
Adult Patients ◽  
Clinical Activity ◽  
Open Label ◽  
North East

BackgroundMTL-CEBPA is a novel immunotherapy targeting the myeloid cell lineage which has shown promising clinical activity as monotherapy and combination therapy with tyrosine kinase inhibitors in hepatocellular carcinoma (HCC). Immunosuppressive myeloid cells are associated with worse outcomes to checkpoint inhibitors. Pre-clinical data have shown that MTL-CEBPA potentiates the oncological effect of PD-1 inhibitors.MethodsThis phase 1A/B, first-in-human, open-label, multicenter study evaluates the safety, tolerability, PK, and efficacy of MTL-CEBPA in combination with a pembrolizumab in adult patients with advanced solid tumours across 3 dose cohorts (70mg/98mg/130mg/m2 MTL-CEBPA once weekly for 3 consecutive weeks with final week break per cycle, with 200mg pembrolizumab every 3 weeks). The primary endpoint is safety and ORR; key secondary endpoints include PK, CR rate & DCR. Key inclusion criteria: Patients with advanced solid tumours who have progressed on standard of care therapy or for whom no standard therapy is available, measurable disease, ECOG PS <2, life expectancy >3 months. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).Results10 pts (3 men, 7 women; median age 50.5yrs), all with different tumor types (1 each of triple negative breast, methothelioma, squamous thymic, cholangiocarcinoma, eccrine, fibrolamellar hepatocellular, colorectal, pancreatic and 2 platinum resistant high-grade serous ovarian). 4 pts had ≥4 prior lines of treatment. All pts reported treatment-related AEs, 7 pts reported AEs considered related to MTL-CEBPA only and all were grade 1 or 2. The most common was nausea (n=3) followed by anaemia, headache, insomnia, neutropenia, pyrexia, transaminase increase and ventricular extrasystole (all n=1). Five pts reported AEs considered related to pembrolizumab only, 2AEs in 1 pt only were grade 3 (ALT and AST increases) There were no DLTs, SAEs or AEs leading to discontinuation or to death in the study. Tumor response was evaluated in 9 pts. 2 pts had a PR (epithelioid mesothelioma at 2 months with 83% tumour reduction, pt ongoing at 9 months & serous ovarian cancer at 2 months with 69% reduction in tumour, pt progressed at 6 months). Three pts had SD, 4 pts had PD as BOR, and 4 pts are continuing to receive treatment.ConclusionsMTL-CEBPA in combination with pembrolizumab demonstrated manageable toxicity at the dose levels tested and has shown antitumor activity. MTD was not reached and RP2D was determined at 130mg/m2 on day 1, 8 and 15 of a 28 day cycle. Enrolment into the dose expansion is ongoing.Trial RegistrationThis study was registered with ClinicalTrials.gov, number NCT04105335.Ethics ApprovalThe study was approved by the North East - Newcastle & North Tyneside 2 Research Ethics Committee, approval number 19/NE/0312.

High Response Rates with the Combination of Bortezomib, Dexamethasone and the Pan-Histone Deacetylase Inhibitor Romidepsin in Patients with Relapsed or Refractory Multiple Myeloma in a Phase I/II Clinical Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3698-3698 ◽  
Author(s):  
Simon James Harrison ◽  
Hang Quach ◽  
Kally Yuen ◽  
Andrew Strayer ◽  
Michael C. Copeman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase I ◽  
Histone Deacetylase ◽  
Dose Escalation ◽  
Response Rate ◽  
Median Number ◽  
High Response ◽  
Clinical Activity ◽  
Synergistic Activity

Abstract INTRODUCTION: Proteasome inhibitors (PI) and histone deacetylase inhibitors (HDACi) have demonstrated synergistic pre-clinical activity in multiple myeloma (MM). The goals of this study were to evaluate this combination regimen’s clinical activity and adverse events, including thrombocytopenia (TCP) since both drug classes may cause transient TCP. We performed an open label, single-centre, single-arm, phase I/II, dose-escalation trial of bortezomib, dexamethasone and romidepsin (depsipeptide) in relapsed or refractory MM. This is the first clinical trial to combine these 3 agents. METHODS. All patients (pts) received bortezomib (1.3mg/m2 d1, 4, 8, 11) with dexamethasone (20mg d1, 2, 4, 5, 8, 9, 11, 12). Romidepsin commenced at 8 mg/m2 IV d1, 8, and 15 every 28 days with a planned accelerated intra-patient dose escalation to 10, 12 and 14 mg/m2 (n=10). After CR + 2 cycles or a maximum of 8 cycles, pts with SD or better commenced maintenance (Mx) therapy, romidepsin at the MTD on days 1 and 8 of a 28 day cycle until PD. An additional 15 pts were treated at the MTD in a phase II expansion. Response was assessed after every 2 cycles according to IMWG criteria (with minimal Response (MR) defined as ≥25% but <50% reduction in M protein). Toxicities were assessed using NCI-CTCAE version 3. RESULTS: In total, 25 pts have been enrolled of which 18 have completed more than 2 cycles and are evaluable for response. The median number of prior regimens was 2 (2–5). Most pts were treated previously with autologous stem cell transplantation (n=11) and neurotoxic regimens; VAD (n=10), thalidomide (n=12), bortezomib (n=6) and lenalidomide (n=4). The median number of treatment cycles delivered was 4 (1–8); Mx cycles 6 (3–15). 10 patients entered the Phase 1 study. No DLTs occurred at 8mg/m2 (n=1) or 10mg/m2 (n=6) of romidepsin. At 12mg/m2 (n=3), TCP (Grade 4, n=3), febrile neutropenia (n=1), peripheral neuropathy (PN) (n=1) and constipation (n=1) DLTs were observed. Of note, 2 pts with Grade 4 TCP had platelets 50–100×109/L before commencing therapy. The MTD for this regimen was determined as romidepsin (10mg/m2) with bortezomib (1.3mg/m2). Other drug-related toxicities observed included: Grade 3: fatigue (n=2), neutropaenia (n=1), sepsis (n=2), PN (n=1); Grade 2: PN (n=6), nausea (n=1). Five pts required bortezomib dose reductions because of PN (n=4). Two pts required a romidepsin dose reduction because of fatigue (n=1) and abnormal LFTs (n=1). The overall response rate (ORR) is 12/18 (67%) (4 CR/nCR, 4 VGPR, 4 PR) with an additional 5 (28%) patients achieving an MR. To date, 7 patients have entered the romi Mx phase. Pt numbers 1, 2, 6, 7, 9, 10 and 11 been on Mx for 15, 3, 12, 8, 7, 4, and 5 months respectively. Four pts have progressed after C1 (n=2), C4 (n=1) and C8+3Mx (n=1). Of note, 3 pts have entered this trial having progressed on a separate trial examining bortezomib maintenance therapy (study protocol PMCC 05/69). These 3 pts were receiving 2 weekly bortezomib and progressing. On the introduction of bortezomib/dexamethasone/romidepsin, the M band has fallen in all assessable pts [41 to 26 (C2); 16 to 11 (C2); 1 pt has not completed C1]. CONCLUSION. This combination of a bortezomib and dexamethasone with romidepsin is well tolerated, with similar TCP compared to single agent bortezomib and romidepsin and demonstrates substantial efficacy in a heavily pre-treated group of patients. The high response rate (OR 67% + 28% MR), impressive depth of response (44% CR + VGPR), durable responses and the observation of a drop in M band in pts progressing on bortezomib as their immediate prior therapy, all indicate that romidepsin has synergistic activity with bortezomib-dexamethasone.

Phase I/II study of the combination of 5-azacytidine(5-AC), all-trans retinoic acid (ATRA) and valproic Acid (VPA) in patients with myelodysplastic syndrome (MDS) and leukemia

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6563-6563
Author(s):  
A. O. Soriano ◽  
H. Yang ◽  
S. Verstovsek ◽  
W. Wierda ◽  
C. Koller ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Performance Status ◽  
Median Number ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Dna Hypomethylation ◽  
Platelet Recovery ◽  
Hypomethylating Agent ◽  
And Performance

6563 Background: The combination of a hypomethylating agent with a histone deacetylase inhibitor (HDACI) has synergistic activity. The combination of ATRA with either a hypomethylating agent or a HDACI restores ATRA sensitivity in resistant cells. The combination of VPA and ATRA has activity in patients with MDS. Based on this, we developed a phase I/II study of the combination of 5-AC, VPA and ATRA for patients with MDS or AML. Methods: The dose of 5-AC was fixed: 75 mg/m2 sq daily × 7. ATRA dose was: 45 mg/m2 orally daily × 5 starting on day 3. Three dose levels of VPA were studied: 50, 62.5 and 75 mg/kg orally daily × 7. The phase I portion of the study followed a 3+3 design. Patients with high risk MDS (≥10% blasts) or relapsed/refractory AML and patients older than 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible. Results: Nineteen patients were registered and 16 were evaluable. Median age was 68 years (5–78). All, but one patient with MDS had AML. Median number of prior therapies was 2 (0–5). Twelve patients (75%) had abnormal cytogenetics. At a VPA dose of 50 mg/kg, 1 of 6 patients developed grade 3 confusion; at 62.5 mg/kg, 0 of 6, and at 75 mg/kg, 2 of 6. One patient had a CR, 2 a complete marrow response (marrow blasts < 5%), and 1 a CRP (same criteria as of CR but without complete platelet recovery), overall response rate was 30% of 13 patients that have completed 1 course. All 4 responses occurred during the first cycle. The CR occurred at a VPA dose of 75mg/kg. The other 3 responses occurred at 62.5 and 75 mg/kg. One out of 2 previously untreated older patients achieved a CR. To assess the hypomethylating effect of 5-AC, we used the LINE assay. Median LINE methylation pretreatment was 62.5% (57–67%), declined to 58% by day 7 and returned to baseline by day 0 of next cycle (p<0.001). Analysis of histone acetylation and gene re-expression are ongoing. Conclusions: The combination of 5-AC with VPA and ATRA is well tolerated. The dose of 62.5 mg/kg daily × 7 is currently being expanded. Significant clinical activity was observed and the effects are potentially mediated by the synergistic action of the combination including induction of DNA hypomethylation and histone acetylation. [Table: see text]

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