CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD > 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., > 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

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Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.66.130 ◽

2005 ◽

Vol 23 (23) ◽

pp. 5314-5322 ◽

Cited By ~ 347

Author(s):

Stephen Chan ◽

Max E. Scheulen ◽

Stephen Johnston ◽

Klaus Mross ◽

Fatima Cardoso ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Adverse Events ◽

Dose Level ◽

Locally Advanced ◽

Metastatic Breast ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Time To Tumor Progression

Purpose In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. Patients and Methods Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. Results Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). Conclusion In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

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Clinical Response in Heavily Pretreated Mycosis Fungoides with Pembrolizumab: A Case Report

Acta Haematologica ◽

10.1159/000518815 ◽

2021 ◽

pp. 1-3

Author(s):

Ginevra Lolli ◽

Beatrice Casadei ◽

Lisa Argnani ◽

Alessandro Pileri ◽

Cinzia Pellegrini ◽

...

Keyword(s):

Mycosis Fungoides ◽

Assessment Tool ◽

Therapeutic Option ◽

Rapid Responses ◽

Duration Of Response ◽

Heavily Pretreated ◽

Stage Ia ◽

Pretreated Patients ◽

Grade 3 ◽

The Moment

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity.

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Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽

10.1182/blood-2020-143143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Claudio Cerchione ◽

Lucio Catalano ◽

Davide Nappi ◽

Anna Emanuele Pareto ◽

Gerardo Musuraca ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Novel Agents ◽

Hematologic Toxicity ◽

Salvage Regimen ◽

Good Compliance ◽

Impressive Result ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3

Background Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Conclusions Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Lucchesi: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

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Safety Profile of Idelalisib in Patients with Refractory Follicular Lymphoma: Interim Analysis of a Noninterventional Study

Blood ◽

10.1182/blood-2020-137607 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-50

Author(s):

Gilles Salles ◽

Ka Lung Wu ◽

Sofya Kovalchuk ◽

Santiago Mercadal ◽

Annalisa Chiarenza ◽

...

Keyword(s):

Follicular Lymphoma ◽

Safety Profile ◽

Interim Analysis ◽

Research Funding ◽

Stage Iii ◽

Disease Stage ◽

Stevens Johnson Syndrome ◽

Risk Of Death ◽

Registration Trial ◽

Grade 3

Introduction: Idelalisib, a selective oral inhibitor of PI3Kδ, was approved by the FDA and EMA as monotherapy for patients with advanced follicular lymphoma (FL) based on positive efficacy and safety results from the registration phase 2 trial in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to 2 prior regimens (NCT01282424; 101-09). Phase 3 studies of idelalisib in earlier lines of treatment for iNHL were terminated prematurely due to an increased risk of death and higher incidence of serious adverse events (AEs) associated with idelalisib. Herein, we present the preplanned interim results as of June 8, 2020, of the safety of idelalisib monotherapy in patients with refractory FL treated in the EU from one of the largest noninterventional trials of idelalisib. Methods: This was a noninterventional, partially retrospective cohort study conducted in 10 European countries (EUPAS19618; NCT03568929). Eligible patients were adults aged ≥18 years treated with idelalisib for refractory FL, per the Summary of Product Characteristics and treatment guidelines, in routine clinical practice. Data was collected from patients' medical records and anonymized. Safety events were evaluated and included treatment-emergent AEs (TEAEs), health outcomes of interest (HOIs) requested by the EMA (bowel perforations, Grade ≥3 diarrhea/colitis, progressive multifocal leukoencephalopathy, pneumonitis, Grade ≥3 rash, infections, Stevens-Johnson syndrome, transaminase elevations, and hepatocellular injury), and deaths. TEAEs were defined as AEs that occurred between first dose and 30 days after last dose. Data were summarized using descriptive statistics. Rates per person-year were calculated as the number of patients experiencing an AE divided by the person-time at risk. Results: For the 158 patients included in this analysis, median age was 67 years and 84 (53%) were male. A summary of patient and disease characteristics at baseline are presented in Table 1. At treatment initiation, 47 (30%) patients had grade 2 FL and 105 (66%) had Ann Arbor stage III/IV disease, though these characteristics were not captured for 42% and 20% of patients, respectively; 149 (94%) had ≥2 prior therapies. The median duration of idelalisib exposure was 165 (range 11-1321) days, and patients were observed for a median of 323 (range 12-1676) days. In total, 144 (91%) patients experienced a TEAE, with a rate of 3.36 per person-year. The proportion of patients experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Table 2. Diarrhea of any grade was the most common TEAE, and infections were the most common treatment-emergent HOI. During the TEAE period, 19 (12%) patients died (Table 2). The proportion of common TEAEs reported in this analysis were lower compared with a subgroup analysis of patients with FL from the registration trial (Salles Haematologica 2017; DOI: 10.3324/haematol.2016.151738), including diarrhea 27% vs 51%, cough 9% vs 32%, fever/pyrexia 10% vs 29%, pneumonia 5% vs 11%; treatment-emergent Grade 3/4 diarrhea/colitis and transaminase elevations were also lower in this analysis: 8% vs 17% and 4% vs 14%. This comparison is limited due to differences in study populations, namely that patients in the registration trial had more advanced disease (stage III/IV, 66% vs 83%) and had a higher median number of prior therapies (3 vs 4). Conclusions: This interim analysis of the safety of idelalisib in patients with refractory FL in this large noninterventional safety study provides an estimate of potential final study findings. The AE profile from this study appears to corroborate the known safety profile of idelalisib. No new safety signals were detected. Disclosures Salles: Bristol Myers Squibb: Consultancy, Other; Genmab: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other. Pettengell:Celgene: Honoraria; MEI Pharma: Honoraria; Roche Ltd: Honoraria; Takeda: Honoraria. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Abbvie: Other: travel grants, Research Funding; Gilead: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Corradini:Kiowakirin: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other; BMS: Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other. De Belder:Gilead Sciences Europe, Ltd.: Current Employment. Shah Gupta:Gilead Sciences, Ltd.: Current Employment. van Troostenburg:Gilead Sciences GmbH: Current Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Current Employment. Ramroth:Gilead Sciences, Ltd.: Current Employment.

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ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study

Blood ◽

10.1182/blood.v118.21.1860.1860 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1860-1860 ◽

Cited By ~ 5

Author(s):

Jatin J Shah ◽

Jeffrey Zonder ◽

Adam Cohen ◽

Robert Z. Orlowski ◽

Raymond Alexanian ◽

...

Keyword(s):

Multiple Myeloma ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Phase 1 ◽

Phase 1 Study ◽

Acceptable Safety Profile ◽

Heavily Pretreated ◽

Grade 3

Abstract Abstract 1860 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY-520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design. Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43–79) and a median of 6 prior regimens (range 2–16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant. The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G-CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G-CSF support was conducted and the MTD for ARRY-520 with G-CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed. ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY-520 has been dosed over extended periods of time (to date, median 7 cycles [range 1–44]), with no evidence of cumulative toxicity. The plasma concentrations of ARRY-520 were determined over a 7-day period during Cycle 1 following the Day 1 and 2 infusions of ARRY-520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going. ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2–8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY-520 was prolonged, with a median time to PR of 3.7 mos (range 3.7–8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs. Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY-520 at 1.5 mg/m2/day with G-CSF support. Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Litwiler:Array BioPharma: Employment. Karan:Array BioPharma: Employment. Hilder:a: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Lonial:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

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A phase II trial of bevacizumab and capecitabine combination in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14555 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14555-14555

Author(s):

P. Zoran ◽

D. Tarabar ◽

R. Doder

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Drug Regimen ◽

Survival Duration ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Third Line ◽

Grade 3

14555 Background: This is a phase II study combination of capecitabine plus bevacizumab for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. Methods: The dose of capecitabine was 1000 mg/m2, administered twice daily for 14 days every 3 weeks. Bevacizumab was given at a dose of 5mg/kg on day 1 as i.v. infusion every 3 weeks. Treatment was repeated until the occurrence of disease progression or unaccepted toxicity. Results: Twenty-eight patients were enrolled. Of 28 patients, the overall response rate was 14.3% and the disease control rate was 42.9%. With a median follow-up period of 7 months, median time to progression and overall survival duration were 3 months and 14 months, respectively. The 1-year survival rate of all patients was 60.7%. The most common treatment-related grade 3/4 hematological toxicities included leukopenia/neutropenia in 4 patients and thrombocytopenia in 3 patients. Nonhematologic toxicities attributable to bevacizumab included bleeding in 3 patients, hypertension in 4 patients, thromboses in 3 patients, proteinuria in 5 patients, and gastrointestinal perforation in 1 patient. Conclusions: This drug regimen was well tolerated and combination of bevacizumab and capecitabine shows potential as third line chemotherapy in heavily pretreated patients with metastatic colorectal cancer. No significant financial relationships to disclose.

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A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2539 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2539-2539

Author(s):

N. Isambert ◽

G. Spitaleri ◽

P. Fumoleau ◽

C. Noberasco ◽

C. Ramazeilles ◽

...

Keyword(s):

Repeated Administration ◽

Individual Variability ◽

Distribution Volume ◽

Weekly Schedule ◽

Cell Cycle Inhibitor ◽

Terminal Half Life ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Tumor Types

2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle). [Table: see text]

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Results of a phase Ib trial evaluating the safety and clinical activity of sapanisertib (TAK 228) in combination with serabelisib (TAK 117) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3604 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3604-3604

Author(s):

Casey B. Williams ◽

Kirstin Anne Williams ◽

Amy K. Krie ◽

Pradip De ◽

Nandini Dey ◽

...

Keyword(s):

Clinical Results ◽

Clinical Activity ◽

Open Label ◽

Effective Treatment Option ◽

Taxane Resistance ◽

Phase 2 Study ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Dose Reductions

3604 Background: The link between taxane resistance and activation of PI3K/AKT/mTOR signaling suggests that by inhibiting this pathway in combination with anti-microtubule agents like paclitaxel may improve treatment outcomes in many malignancies. To investigate this further we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial to determine the safety, efficacy, and RP2D. Methods: Open label, cohort study using a traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts. A dose expansion of cohort 4, the recommended RP2D, is planned for February 2020. Results: Enrollment to the DLT evaluation has been completed and the clinical results are summarized in Table. Sixteen patients have been enrolled; a majority were heavily pretreated and resistant to paclitaxel. Overall, the combination was safe and tolerable. One DLT occurred due to renal dysfunction in cohort 5. 360 adverse events have been reported, but only 28 (8%) grade 3 or 4 events. The most common events were leukopenia and non-febrile neutropenia. Two patients required dose reductions as a result of pneumonitis. The ORR is currently 46% in 13 evaluable patients. CBR is 69% and PFS is currently at 10 months. Two patients achieved a CR and three patients remain on treatment. Conclusions: The combination proved to be well tolerated in the doses and schedules used in cohorts 1-4 and exhibited very promising clinical activity in heavily pretreated patients. This regimen could prove to be a highly effective treatment option and a phase 2 study is warranted at the RP2D. Clinical trial information: NCT03154294 . [Table: see text]

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Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽

10.1182/blood-2021-153971 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5022-5022

Author(s):

Claudio Cerchione ◽

Lucio Catalano ◽

Davide Nappi ◽

Anna Emanuele Pareto ◽

Fabrizio Pane ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Novel Agents ◽

Hematologic Toxicity ◽

Salvage Regimen ◽

Good Compliance ◽

Impressive Result ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3

Abstract Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Martinelli: Stemline Therapeutics: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Astellas: Consultancy, Speakers Bureau.

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An Exploration of Trifluridine/Tipiracil in Combination with Irinotecan in Patients with Pretreated Advanced Gastric Cancer

10.21203/rs.3.rs-1143619/v1 ◽

2021 ◽

Author(s):

Takuro Mizukami ◽

Keiko Minashi ◽

Hiroki Hara ◽

Tomohiro Nishina ◽

Yusuke Amanuma ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Treatment Options ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Recommended Phase Ii Dose

Abstract Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer but with limited efficacies. We investigated the combination of FTD/TPI and irinotecan for such patients.Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used an escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on days 1 and 15] with 2 schedules of FTD/TPI 35 mg/m2/dose: twice daily, on days 1-5 and 8-12 (Level A) or on days 1-5 and days 15-19 (Level B) of a 28-day cycle. The primary and secondary objectives were determination of maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) , and evaluation of disease control rate (DCR), respectively. Results: Eleven patients were enrolled; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A, and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively.Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation for its efficacy in the RP2D is necessary. Mini-abstract: A phases Ib study of trifluridine/tipiracil in combination with irinotecan for advanced gastric cancer determined the recommended dose with manageable hematologic toxicities and feasible non-hematologic toxicities.

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