Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial

Introduction Event free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30-50%, with 5-year survival for adult patients only 20%. A large proportion of patients with newly diagnosed and relapsed ALL harbour somatic mutations that activate the RAS-signalling cascade. Steroids are a backbone of all induction blocks of ALL therapy, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886), results in a potent synergistic anti-cancer effect. Methods and analysis The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Munster, Germany; Paris, France; and Utrecht, Netherlands. Paediatric centres are all part of the Innovative Therapies for Children with Cancer consortium. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are >18 years old, ECOG <2 and paediatric <18 years old, Lansky play scale ≥60% or Karnofsky score ≥60%. The primary objective in phase I is to determine the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method, and phase II will evaluate preliminary anti-leukaemic activity of the selumetinib/dexamethasone combination, as defined by morphological response 28 days post treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum of 13 and maximum of 21 in each group), depending on how many phase I patients are included also in phase II. Ethics and dissemination Medical ethical committees of all the participating countries will approve the study protocol. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. Trial registration number The trial was registered on EudraCT 2016-003904-29 on 21st September 2016, ISRCTN 92323261, ClinicalTrials.Gov NCT03705507, and ITCC-063 study.

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A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia

British Journal of Haematology ◽

10.1111/j.1365-2141.2011.08762.x ◽

2011 ◽

Vol 154 (4) ◽

pp. 471-476 ◽

Cited By ~ 67

Author(s):

John Schindler ◽

Srikanth Gajavelli ◽

Farhad Ravandi ◽

YuMin Shen ◽

Samir Parekh ◽

...

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

Phase I ◽

Lymphoblastic Leukaemia ◽

Phase I Study ◽

Adult Patients ◽

B Lineage

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Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study

The Lancet Oncology ◽

10.1016/s1470-2045(14)71170-2 ◽

2015 ◽

Vol 16 (1) ◽

pp. 57-66 ◽

Cited By ~ 638

Author(s):

Max S Topp ◽

Nicola Gökbuget ◽

Anthony S Stein ◽

Gerhard Zugmaier ◽

Susan O'Brien ◽

...

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Adult Patients ◽

Phase 2 ◽

Phase 2 Study

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Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.8406 ◽

2006 ◽

Vol 24 (1) ◽

pp. 136-140 ◽

Cited By ~ 20

Author(s):

Andrew J. Vickers ◽

Joyce Kuo ◽

Barrie R. Cassileth

Keyword(s):

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase Ii ◽

Dose Finding ◽

Phase Iii ◽

High Dose ◽

Free Text ◽

Phase Ii Trials ◽

Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

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Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia

British Journal of Haematology ◽

10.1111/j.1365-2141.2005.05544.x ◽

2005 ◽

Vol 130 (2) ◽

pp. 166-173 ◽

Cited By ~ 41

Author(s):

James Nachman

Keyword(s):

Young Adult ◽

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Clinical Characteristics ◽

Adult Patients

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Incidence of thrombotic complications in adult patients with acute lymphoblastic leukaemia receiving L-asparaginase during induction therapy: A retrospective study

European Journal Of Haematology ◽

10.1111/j.1600-0609.1992.tb00032.x ◽

2009 ◽

Vol 49 (2) ◽

pp. 63-66 ◽

Cited By ~ 80

Author(s):

Luigi Gugliotta ◽

Maria-Gabriella Mazzucconi ◽

Giuseppe Leone ◽

Monica Mattioli-Belmonte ◽

Daniela Defazio ◽

...

Keyword(s):

Retrospective Study ◽

Acute Lymphoblastic Leukaemia ◽

Induction Therapy ◽

Lymphoblastic Leukaemia ◽

Adult Patients ◽

Thrombotic Complications

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Phase I combination dose-finding/phase II expansion cohorts of lenvatinib + etoposide + ifosfamide in patients (pts) aged 2 to ≤ 25 years with relapsed/refractory (r/r) osteosarcoma

Annals of Oncology ◽

10.1093/annonc/mdz283.009 ◽

2019 ◽

Vol 30 ◽

pp. v688 ◽

Cited By ~ 3

Author(s):

N. Gaspar ◽

F J Bautista Sirvent ◽

R. Venkatramani ◽

A. Longhi ◽

C. Lervat ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Dose Finding

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Outcome after first relapse in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia

British Journal of Haematology ◽

10.1111/bjh.12225 ◽

2013 ◽

Vol 161 (1) ◽

pp. 95-103 ◽

Cited By ~ 7

Author(s):

Shinichi Kako ◽

Heiwa Kanamori ◽

Naoki Kobayashi ◽

Akio Shigematsu ◽

Yasuhito Nannya ◽

...

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Philadelphia Chromosome ◽

Adult Patients ◽

First Relapse

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Innovative Phase I/II Statistical Design in Combination Chemotherapy That Combines Toxicity and Efficacy Parameters to Increase Study Efficiency: Bendamustine and Idarubicin in De Novo Adult AML

Blood ◽

10.1182/blood.v118.21.1552.1552 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1552-1552

Author(s):

Jack M. Lionberger ◽

Kathleen Shannon Dorcy ◽

Carol Dean ◽

Nathan Holm ◽

Bart Lee Scott ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

De Novo ◽

Statistical Design ◽

Maximum Tolerated Dose ◽

Dose Finding ◽

Therapeutic Decisions ◽

Number Of Patients ◽

Relevant Dose ◽

Acceptable Probability

Abstract Abstract 1552 Background: Novel drugs or drug combinations are conventionally tested first in Phase I studies (in which therapeutic decisions are based solely on toxicity) with Phase II (efficacy) evaluations following as a separate trial. This process not only slows new drug development, it is challenging for patients during the informed consent process, because they usually enter trials not merely in hope of “no toxicity” but in hope of response. Response rates in Phase I at doses less than the maximum tolerated dose (MTD) may be irrelevant to efficacy, but this common assumption remains unproven. An equally plausible alternative is efficacy failure at these lower doses augurs failure at the MTD in Phase II. This hypothesis prompted development of a Phase I-II Bayesian design that uses both efficacy and toxicity to find a clinically relevant dose (Biometrics 2004;60: 684–93). In the current study, we apply the innovative Bayesian approach to the design of a Phase I-II trial using bendamustine + idarubicin in older patients (>50 yo) with newly-diagnosed AML or high risk MDS (>10% marrow blasts). We then compare and contrast our trial operation with that of the standard 3+3 Phase I design. Methods: The design specifies anticipated probabilities (“priors”) of response (CR or no CR) and toxicity (grade 3–4 or not) at each of 4 doses of bendamustine (45,60,75,90 mg/m2 daily × 5 together with idarubicin 12 mg/m2 daily on day 1 and 2). Patients are entered in groups of 3 beginning at the 45 mg/m2 dose. As response/toxicity data became available for each cohort, Bayes theorem is used to update the priors and derive current probabilities (“posteriors”) of response/toxicity at each dose. The priors are set to be relatively non-informative allowing the posteriors to be primarily influenced by the data from the trial. The posteriors are referred to a minimum acceptable probability of response (here 40%) and a maximum acceptable probability of toxicity (30%). If the posteriors indicate that it is highly unlikely (< 2% chance) that any dose is associated with both of these probabilities the trial stops. Otherwise the next cohort of patients is treated at a dose so associated. This process is repeated iteratively to a maximum sample size of 48 patients. The parameters noted above were chosen to give desirable probabilities of selecting for future study doses meeting the minimum acceptable response and maximum acceptable toxicity rates. Results: Table 1 compares the operation of this trial with a standard 3+3 Phase I trial. Given that 2/3 patients had toxicity at the 75 dose, a Phase I 3+3 design would have declared 60 the MTD. Subsequently, an “expansion cohort” as a Phase II trial would be treated at this dose without any possibility of revisiting the 75 dose. This conclusion flies in the face of basic notions of statistical reliability and ignores the possibility that patients experiencing toxicity may have been particularly old, had significant comorbidities, or have a variable functional reserve for undefined reasons. In contrast, the Phase I-II design allows the trial to continue, and potentially revisit higher doses of therapy depending on the collective outcome of a greater number of patients. Based on our actual data, this trial continued to treat patients at the 60 mg/m2 dose level, and in the next three patients there was no toxicity. In this case response data becomes the determining factor, which improves the efficiency of the trial. If 0/3 patients had a response, the trial would return to 75 mg/m2, however, because 2/3 patients had a response, the trial continues to accrue at 60mg/m2, with the statistical force of twice the number of patients. Conclusion: Accounting for response during dose finding seems to permit more sophisticated/flexible decisions about dosing in addition to improving efficiency. Disclosures: Shannon Dorcy: Cephalon: Consultancy, Honoraria, Speakers Bureau.

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Rituximab-CHOP21 Plus Lenalidomide (LR-CHOP21) Is Effective and Feasible in Elderly Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of Phase II REAL07 Study of the Fondazione Italiana Linfomi (FIL)

Blood ◽

10.1182/blood.v120.21.903.903 ◽

2012 ◽

Vol 120 (21) ◽

pp. 903-903

Author(s):

Annalisa Chiappella ◽

Silvia Franceschetti ◽

Alessia Castellino ◽

Angelo Michele Carella ◽

Ileana Baldi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Board Of Directors ◽

Phase Ii ◽

Phase Ii Study ◽

Dose Finding ◽

Phase Iii ◽

Advisory Committees ◽

Off Label ◽

Grade Iii

Abstract Abstract 903 Introduction. R-CHOP21 is the standard treatment for untreated elderly DLBCL, however up to 40% of patients fail. There is a need to improve the efficacy of R-CHOP21; an option may be the addition of novel drugs in first line induction therapy. Lenalidomide has a complex mechanism of action as immunemodulation, antiangiogenesis, restoration of immunesynapses and direct antitumor effects. Lenalidomide monotherapy exhibits significant activity in patients with relapsed aggressive B-cell NHL and has in vitro synergy with rituximab and cytotoxic therapy. This rationale prompted FIL to conduct a prospective multicenter dose finding phase I-II trial aimed at evaluating toxicity and activity of lenalidomide plus R-CHOP21 (LR-CHOP21) in elderly untreated DLBCL (NCT00907348). In the dose-finding phase I study, 21 patients were enrolled, and 15 mg lenalidomide from day 1 to day 14 was identified as the maximum tolerated dose (MTD) in combination with R-CHOP21 (Vitolo, Ann Oncol 2011;22(4):331a). Patients and Methods. Based on the phase I results, 15 mg of lenalidomide in combination to R-CHOP21 was tested in a phase II study. Phase II was designed according to Simon's two stage design; primary endpoint was an improvement of overall response rate (ORR) of 15% in LR-CHOP21 compared to 70% of standard R-CHOP21 and the study would be considered of interest if at least 16/23 in step 1 and 39/49 in step 2 responses occurred. Response was evaluated according to 2007 Cheson criteria. PET scan was mandatory at the end of the treatment; patients in partial remission (PR) who underwent radiotherapy were considered as failure in progression free survival (PFS) analysis. Inclusion criteria were: age 60–80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; IPI at LI/IH/H risk. Treatment plan was: R-CHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. Mandatory supportive care included: GCSF or PegGCSF, cotrimoxazole as Pneumocystis Jiroveci prophylaxis and low molecular weight heparin or low dose aspirin as deep venous thrombosis prophylaxis. Results. From April 2010 to May 2011, 49 patients were enrolled in the phase II study including 9 patients treated at the MTD during phase I. Clinical characteristics were: median age 69 years (range 61–80); stage III/IV 43 (88%), performance status >1 31 (63%), IPI IH/H 30 (61%). The step-1 of the trial showed an ORR of 22/23. At the end of 6 LR-CHOP21, ORR was 45/49 (92%). Complete remissions (CR) were 42 (86%) and PR 3 (6%); 3 patients (6%) did not respond and one (2%) died for violent death. At a median follow-up of 18 months, overall survival (OS) was 94% (95% CI: 82–98) and PFS was 75% (95% CI: 57–86). (Figure 1). Of the 294 planned courses of LR-CHOP21, 277 (94%) were administered, of which 221 (75%) with lenalidomide as planned, 40 (14%) with dose and/or day reduction and 16 (5%) without lenalidomide. Median dose of lenalidomide delivered in 49 patients was 1185 mg (IQR 900–1260), i.e. 94% of the planned dose (1260 mg). The most frequent cause of lenalidomide reduction or withdrawal was neutropenia. At least 90% of the planned dose of doxorubicine, cyclophosphamide and vincristine were administered, in: 91%, 95% and 83% of the R-CHOP21 courses, respectively. Median interval time between R-CHOP21 courses was 21 days (range 19–48). Hematological toxicity was mild: grade III/IV thrombocytopenia occurred in 13% of courses, anemia in 5% and neutropenia in 33%, with only 4% of febrile neutropenia. No grade IV extra-hematological toxicities were observed. Grade III non-hematological toxicities were reported in 7 patients: cardiologic, gastroenteric and renal in one patient respectively, grade III neurological toxicities, sensory and motorial neuropathy in two, thromboembolic event in one not receiving anti-thrombotic prophylaxis, and skin rash in one. No toxic deaths occurred during treatment. One patient died three months off therapy while in CR, due to aeromonas hydrophila sepsis and multi-organ failure. Conclusions. The addition of 15 mg lenalidomide on days 1–14 to R-CHOP21 is safe, feasible and effective in elderly untreated DLBCL. The primary objective of the phase II study was met, with 92% of ORR of which 86% CR and promising PFS rates. The addition of lenalidomide did not impair the administration of R-CHOP21. Based on these data, the efficacy of LR-CHOP21 needs to be investigated in a large phase III randomized trial in elderly DLBCL. Disclosures: Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Dreyling:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

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