NCT01776723

A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib

Completed Phase 1, PHASE2 Results posted Last updated 22 September 2022

What this trial tests

Phase 1, PHASE2 trial testing Ruxolitinib in Myelomonocytic Leukemia in 50 participants. Completed in 10 May 2022.

Timeline

20 February 2013

Primary endpoint
28 November 2018

10 May 2022

Quick facts

Lead sponsor	H. Lee Moffitt Cancer Center and Research Institute
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	50
Start date	20 February 2013
Primary completion	28 November 2018
Estimated completion	10 May 2022
Sites	6 locations across United States

Drugs / interventions tested

• Ruxolitinib (RUXOLITINIB) — full drug profile →

Conditions studied

• Myelomonocytic Leukemia — all drugs for Myelomonocytic Leukemia →

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Who can join

18 and older, any sex, with Myelomonocytic Leukemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML) Primary · 17 weeks

Phase I - The MTD is defined as the highest dose where less than 33% of participants experience a drug related predefined dose limited toxicity (DLT). Dose-limiting toxicity (DLT) is defined as any grade 4 hematologic toxicity and any grade 3 or greater non-hematologic toxicity except nausea that is controlled by antiemetic therapy based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are adequately controlled within 72 hours are not to be considered a DLT.

Group	Value	95% CI
I: Dose Escalation - Ruxolitinib	40

Occurrence of Clinical Response Primary · Up to 2 years

Phase II - Proportion of participants achieving clinical benefit defined as hematologic improvement, complete remission (CR), partial remission (PR), marrow complete remission (Marrow CR) or stable disease (SD) by the International Working Group (IWG) 2006 criteria. Erythroid Response for pretreatment hemoglobin \< 11 g/dl; Platelet response for subjects with a pre-treatment platelet count \< 50 x 10\^9/L; Neutrophil response with pretreatment absolute neutrophil count (ANC) \< 1 x 10\^9/L.

Group	Value	95% CI
II: Maximum Tolerated Dose - Ruxolitinib	18

Percentage of Participants With Acute Myeloid Leukemia (AML) Transformation Secondary · Up to 2 years

Phase II - To determine the time to AML transformation of participants on Ruxolitinib. Acute myeloid leukemia (AML) transformation according to World Health Organization (WHO) criteria. CMML-1: peripheral blood \<5% blasts, bone marrow \<10% myeloblast. CMML-2: peripheral blood \<19 percent blasts persistent monocytosis \>1000/ul +/- cytopenias Leukocytosis frequent, bone marrow \<19 percent blasts \>10% dysplasia in affected lineage, Auer Rods.

Group	Value	95% CI
All Participants	14

Median Overall Survival (OS) Secondary · Up to 2 years

Phase II - To determine the median overall survival.

Group	Value	95% CI
II: Maximum Tolerated Dose - Ruxolitinib	23.7	13.3 – 30

Duration of Response in Days Secondary · 3.5 years

Phase II - To determine the duration of response achieved as in secondary endpoint one. The duration of response is measured from the time measurement criteria are met for major or complete platelet response (which ever is first recorded) until the first date that disease progression defined by the bone marrow response outlined above, progression/relapse following a CR, marrow CR or PR, or progressions/relapse following hematological improvement (HI) as outlined above.

Group	Value	95% CI
Phase 1, Level 1: Ruxolitinib 10 mg	104	55 – 172
Phase 1, Level 2: Ruxolitinib 20 mg	446.25	28 – 961
Phase 1, Level 3: Ruxolitinib 30 mg	718	54 – 1248
Phase 1, Level 4: Ruxolitinib 40 mg	331.25	60 – 853
Maximum Tolerated Dose - Ruxolitinib	263.5	6 – 874

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events collected from time of consent through follow-up, up to 2 years. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1, Level 1: Ruxolitinib 10 mg

Serious: 6/6 (100%)

Deaths: 6/6

Phase 1, Level 2: Ruxolitinib 20 mg

Serious: 4/4 (100%)

Deaths: 4/4

Phase 1, Level 3: Ruxolitinib 30 mg

Serious: 1/5 (20%)

Deaths: 1/5

Phase 1, Level 4: Ruxolitinib 40 mg

Serious: 1/5 (20%)

Deaths: 1/5

II: Maximum Tolerated Dose - Ruxolitinib

Serious: 15/30 (50%)

Deaths: 13/30

Serious adverse events (36 terms)

Reaction	System	Phase 1, Level 1: Ruxoliti…	Phase 1, Level 2: Ruxoliti…	Phase 1, Level 3: Ruxoliti…	Phase 1, Level 4: Ruxoliti…	II: Maximum Tolerated Dose…
Death NOS	General disorders	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Cardiac arrest	Cardiac disorders	—	—	—	—	—
Flu like symptoms	General disorders	—	—	—	—	—
Facial muscle weakness	Nervous system disorders	—	—	—	—	—
Creatinine increased	Investigations	—	—	—	—	—
Muscle weakness lower limb	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Nervous system disorders - other	Nervous system disorders	—	—	—	—	—
Pulmonary hypertension	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Spleen disorder	Blood and lymphatic system disorders	—	—	—	—	—
Vascular disorders -Other	Vascular disorders	—	—	—	—	—
Heart failure	Cardiac disorders	—	—	—	—	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Respiratory, thoracic and mediastinal disorders - other	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Dehydration	Gastrointestinal disorders	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—
Tumor lysis syndrome	Metabolism and nutrition disorders	—	—	—	—	—

Other adverse events (203 terms — click to expand)

Reaction	System	Phase 1, Level 1: Ruxoliti…	Phase 1, Level 2: Ruxoliti…	Phase 1, Level 3: Ruxoliti…	Phase 1, Level 4: Ruxoliti…	II: Maximum Tolerated Dose…
Anemia	Blood and lymphatic system disorders	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Leukocytosis	Blood and lymphatic system disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Fever	General disorders	—	—	—	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—
Upper respiratory infection	Infections and infestations	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Bruising	Injury, poisoning and procedural complications	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—
Skin and subcutaneous tissue disorders -other	Skin and subcutaneous tissue disorders	—	—	—	—	—
Infections and infestations - Other	Infections and infestations	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—	—	—
Creatinine increased	Investigations	—	—	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—
Respiratory, thoracic and mediastinal disorders - other	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Edema limbs	General disorders	—	—	—	—	—
Pain	General disorders	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Sore throat	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—
Middle ear inflammation	Ear and labyrinth disorders	—	—	—	—	—
Ear and labyrinth disorders -Other	Ear and labyrinth disorders	—	—	—	—	—

Most-reported serious reactions: Death NOS, Fall, Hyperglycemia, Lung infection, Diarrhea, Fatigue, Cardiac arrest, Flu like symptoms.

Data from ClinicalTrials.gov NCT01776723 adverse events section.

Sponsor's own description

The purpose of this study is to find out if treating Chronic Myelomonocytic Leukemia (CMML) with a study drug \[ruxolitinib\] can improve outcomes of patients with CMML. The first step of the study is to learn the dose of ruxolitinib that is tolerable (bearable). It has already been studied in a number of patients with different bone marrow diseases and is approved for the treatment of a disease called Myelofibrosis; however, it is not approved for treatment of CMML. It is given orally (by mouth). Most people tolerate it well but the tolerability has not been determined in patients with CMML. We will be testing different doses to determine how much of the medication people can tolerate (bear) before they develop side effects.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication.
   Loh CY, Arya A, Naema AF, Wong WF, et al · · 2019 · cited 241× · PMID 30847297 · DOI 10.3389/fonc.2019.00048
2. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet.
   Itzykson R, Fenaux P, Bowen D, Cross NCP, et al · · 2018 · cited 94× · PMID 31723789 · DOI 10.1097/hs9.0000000000000150
3. JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition.
   Luo Y, Alexander M, Gadina M, O'Shea JJ, et al · · 2021 · cited 92× · PMID 34625141 · DOI 10.1016/j.jaci.2021.08.004
4. A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML).
   Padron E, Dezern A, Andrade-Campos M, Vaddi K, et al · · 2016 · cited 76× · PMID 26858309 · DOI 10.1158/1078-0432.ccr-15-2781
5. JAK/STAT in leukemia: a clinical update.
   Liang D, Wang Q, Zhang W, Tang H, et al · · 2024 · cited 38× · PMID 38273387 · DOI 10.1186/s12943-023-01929-1
6. Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia.
   Hunter AM, Newman H, Dezern AE, Steensma DP, et al · · 2021 · cited 29× · PMID 34253584 · DOI 10.1158/1078-0432.ccr-21-0935
7. STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer.
   Qureshy Z, Li H, Zeng Y, Rivera J, et al · · 2022 · cited 23× · PMID 35929989 · DOI 10.1158/1078-0432.ccr-22-0744
8. Transcription Factors and Cancer: Approaches to Targeting.
   Shiah JV, Johnson DE, Grandis JR. · · 2023 · cited 18× · PMID 36693157 · DOI 10.1097/ppo.0000000000000639