Buparlisib in Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia

• Sponsor: Canadian Cancer Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT02340780
• Collaborator: Novartis (Industry)
• Enrollment: 14
• Locations: 6
• Arm: 1
• Actual Duration (Months): 62.9
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects a new drug, buparlisib, has on chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Buparlisib	Phase 2

Detailed Description

Buparlisib has been shown to shrink tumours in animals. It has been studied in some people and seems promising but it is not clear if it can offer better results than standard treatment.

The standard or usual treatment for this disease is chemotherapy, targeted therapy or radiation, either alone or in combination.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Buparlisib in Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jan 30, 2015
• Actual Primary Completion Date: Nov 21, 2018
• Actual Study Completion Date: Apr 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Buparlisib 100mg daily orally every 28 days	Drug: Buparlisib

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [30 months]

   To determine the overall response rate (complete + partial response, as defined in the protocol) to oral buparlisib in patients with relapsed and refractory chronic lymphocytic leukemia. Complete Response (CR): CR requires all of the criteria listed on page 31 of the protocol, maintained for a period of at least 8 weeks. Partial Response (PR): To define a PR, at least 1 of the criteria of Group A plus 1 of the criteria of Group B listed on page 32 of the protocol must be met and persist for ≥ 8 weeks, in the absence of any criteria definitive of progressive disease.

Secondary Outcome Measures

1. Progression Free Survival [30 months]

   Progression-free survival (PFS) is defined as the time in months from study entry until disease progression or death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Previously documented CLL that is recurrent or relapsed after previous therapy and that requires treatment

• Age ≥ 18 years

• ECOG Performance Status score of 0, 1 or 2

• Patients must have a life expectancy of at least 12 weeks. Those who have previously completed curative treatment of a malignancy other than CLL will be eligible

• Patients must have at least ONE of: Lymphocyte count ≥ 10 x 10^9/L OR at least one pathologically enlarged lymph node (≥ 2 x 2 cm) by CT scan

• Previous therapy: Patients must have received at least 1 prior systemic treatment regimen (single agent or combination therapy). There is no upper limit on number of prior regimens. Patients who have received prior autologous or allogeneic stem cell transplantation are eligible.

• Patients must have recovered (to ≤ grade 2) from all reversible toxicity related to prior systemic therapy, and have adequate washout from prior chemotherapy and investigational agents defined as the longest of:

• two weeks

• standard cycle length of prior regimen (e.g. 28 days for FCR)

• 5 half-lives for investigational drugs

Not permitted:

• prior treatment with buparlisib (BKM120)

• Patients may have had radiation, provided a minimum of 21 days has elapsed prior to enrollment. Patients must have recovered from any acute toxic effects from radiation prior to registration

• Previous surgery is permitted provided that wound healing has occurred and at least 14 days have elapsed if surgery was major

• Absolute neutrophil counts (ANC): ≥ 1.0 x 10^9/L

• Platelets ≥ 50/min x 10^9/L and more than 5 days since last transfusion

• Creatinine clearance* ≥ 50 mL/min

• Bilirubin** ≤ 1.5 x upper normal limit (UNL)

• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5 x UNL or ≤ 3 x UNL if hepatic involvement with CLL

• Potassium and calcium Within normal limits for laboratory (supplementation permitted)

• Glucose (fasting) < 7.8 mmol/L (AND HbA1c ≤ 8% if diabetic)

• Creatinine clearance as calculated by Cockcroft-Gault formula or by 24 hour urine measurement: Females: GFR = 1.04 x (140-age) x weight in kg serum creatinine in μmol/L Males: GFR = 1.23 x (140-age) x weight in kg serum creatinine in μmol/L

** Direct if patient known to have Gilbert's syndrome

• Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements

• Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre

• In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient registration

Exclusion Criteria:

• Progression to high grade lymphoma (Richter's transformation) or myelodysplasia

• Patients with known hypersensitivity to the study drug or its excipients

• The following are exclusions for enrolment on the study:

• Pregnant or lactating women. (N.B. All women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to registration).

• Men and women of childbearing potential who do not agree to use adequate contraception: prior to study entry; while taking buparlisib and after completion of study therapy for 12 weeks in men and 4 weeks in women.

• Serious illness or medical condition which would not permit the patient to be managed according to the protocol, including, but not limited to:

1. active uncontrolled or serious infection (viral, bacterial or fungal);

2. pulmonary disease requiring oxygen;

3. known HIV infection or other immune deficiency disorders (except for CLL);

4. uncontrolled auto-immune hemolytic anemia (AIHA) or auto-immune thrombocytopenia (ITP)

5. acute or chronic pancreatitis

• Uncontrolled or significant cardiovascular disease including:

• Myocardial infarction within 12 months

• Uncontrolled angina within 6 months

• Clinically significant congestive heart failure (eligible if controlled and LVEF ≥ 50%)

• Stroke, TIA or other ischemic event within 12 months

• Severe cardiac valve dysfunction

• Left ventricular ejection fraction < 50% (only required if symptoms suggestive or history of cardiovascular disease)

• Uncontrolled hypertension

• Patient has any of the following mood disorders:

• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others)

• Score of ≥ 12 on the PHQ-9 questionnaire

• Score of ≥ 15 on the GAD-7 mood scale

• ≥ CTCAE grade 3 anxiety

• Patient selects a positive response of '1,2,3' to question 9 (suicidal ideation) in the PHQ-9 questionnaire

• Patients who have received prior buparlisib (BKM120).

• Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

• Patients who are unable to swallow capsules

• Patients on strong CYP3A inhibitors/inducers or therapeutic doses of warfarin-like anticoagulants (must have discontinued > 7 days prior to day 1). Patients may receive low molecular weight heparin if indicated. See Appendix VII for a list of prohibited medications.

• Patients on drugs with a known risk to induce Torsades de Pointes

• Patients receiving high dose steroid therapy or another immunosuppressive agent. Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients who are on stable moderate dose corticosteroid treatment for treatment of conditions other than CLL (< dexamethasone 4 mg/day, prednisone 25 mg/day) for at least 14 days before start of study treatment are eligible.

• Patients with known HIV positivity.

• Patients with known CLL involvement of the central nervous system.

• Patients with a history of other malignancies, except those which have been curatively treated and require no ongoing therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
2	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
3	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
4	QEII Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 1V7
5	University Health Network	Toronto	Ontario	Canada	M5G 2M9
6	The Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2

Sponsors and Collaborators

• Canadian Cancer Trials Group
• Novartis

Investigators

• Study Chair: Sarit Assouline, McGill University - Dept. Oncology, Jewish General Hospital Site, Montreal QC Canada

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 28, 2017
• Study Protocol - Aug 24, 2016

More Information

Publications

None provided.

• Responsible Party: Canadian Cancer Trials Group
• ClinicalTrials.gov Identifier: NCT02340780
• Other Study ID Numbers: I216
• First Posted: Jan 19, 2015
• Last Update Posted: May 8, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell

Study Results

Participant Flow

Arm/Group Title	Buparlisib
Arm/Group Description	100mg daily orally every 28 days Buparlisib
Period Title: Overall Study
STARTED	14
COMPLETED	13
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Buparlisib
Arm/Group Description	100mg daily orally every 28 days Buparlisib
Overall Participants	13
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	74
Sex: Female, Male (Count of Participants)
Female	5 38.5%
Male	8 61.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	12 92.3%
Unknown or Not Reported	1 7.7%
Performance status (Count of Participants)
Grade 0	5 38.5%
Grade 1	8 61.5%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	To determine the overall response rate (complete + partial response, as defined in the protocol) to oral buparlisib in patients with relapsed and refractory chronic lymphocytic leukemia. Complete Response (CR): CR requires all of the criteria listed on page 31 of the protocol, maintained for a period of at least 8 weeks. Partial Response (PR): To define a PR, at least 1 of the criteria of Group A plus 1 of the criteria of Group B listed on page 32 of the protocol must be met and persist for ≥ 8 weeks, in the absence of any criteria definitive of progressive disease.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

All eligible patients who received the protocol treatment.

Arm/Group Title	Buparlisib
Arm/Group Description	100mg daily orally every 28 days Buparlisib
Measure Participants	13
Response	6 46.2%
Non-response	7 53.8%

2. Secondary Outcome

Title	Progression Free Survival
Description	Progression-free survival (PFS) is defined as the time in months from study entry until disease progression or death.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

All eligible patients who received protocol treatment

Arm/Group Title	Buparlisib
Arm/Group Description	100mg daily orally every 28 days Buparlisib
Measure Participants	13
Median (95% Confidence Interval) [months]	21.65

Adverse Events

Time Frame	30 months
Arm/Group Title	Buparlisib
Arm/Group Description	100mg daily orally every 28 days Buparlisib
All Cause Mortality
	Buparlisib
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	Buparlisib
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Gastrointestinal disorders
Nausea	1/13 (7.7%)
Renal and urinary disorders
Hematuria	1/13 (7.7%)
Surgical and medical procedures
Other surgical and medical procedures	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Buparlisib
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Cardiac disorders
Paroxysmal atrial tachycardia	1/13 (7.7%)
Ear and labyrinth disorders
Hearing impaired	1/13 (7.7%)
Other ear and labyrinth disorders	2/13 (15.4%)
Tinnitus	1/13 (7.7%)
Endocrine disorders
Other endocrine disorders	1/13 (7.7%)
Eye disorders
Blurred vision	2/13 (15.4%)
Cataract	1/13 (7.7%)
Other eye disorders	1/13 (7.7%)
Gastrointestinal disorders
Abdominal pain	1/13 (7.7%)
Constipation	1/13 (7.7%)
Diarrhea	7/13 (53.8%)
Dry mouth	1/13 (7.7%)
Dyspepsia	3/13 (23.1%)
Dysphagia	1/13 (7.7%)
Gastroesophageal reflux disease	2/13 (15.4%)
Hemorrhoids	1/13 (7.7%)
Mucositis oral	3/13 (23.1%)
Nausea	4/13 (30.8%)
Other gastrointestinal disorders	1/13 (7.7%)
General disorders
Chills	1/13 (7.7%)
Edema face	1/13 (7.7%)
Edema limbs	2/13 (15.4%)
Fatigue	8/13 (61.5%)
Fever	1/13 (7.7%)
Irritability	1/13 (7.7%)
Non-cardiac chest pain	1/13 (7.7%)
Other general disorders, administration site conditions	2/13 (15.4%)
Pain	2/13 (15.4%)
Infections and infestations
Lung infection	1/13 (7.7%)
Other infections and infestations	2/13 (15.4%)
Otitis media	1/13 (7.7%)
Sinusitis	1/13 (7.7%)
Skin infection	1/13 (7.7%)
Upper respiratory infection	1/13 (7.7%)
Injury, poisoning and procedural complications
Bruising	2/13 (15.4%)
Fall	1/13 (7.7%)
Other injury, poisoning and procedural complications	1/13 (7.7%)
Investigations
Alanine aminotransferase increased	1/13 (7.7%)
Platelet count decreased	1/13 (7.7%)
Metabolism and nutrition disorders
Anorexia	4/13 (30.8%)
Dehydration	1/13 (7.7%)
Hyperglycemia	4/13 (30.8%)
Musculoskeletal and connective tissue disorders
Back pain	2/13 (15.4%)
Bone pain	2/13 (15.4%)
Generalized muscle weakness	1/13 (7.7%)
Other musculoskeletal and connective tissue disorder	1/13 (7.7%)
Pain in extremity	2/13 (15.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other neoplasms benign, malignant and unspecified	1/13 (7.7%)
Nervous system disorders
Cognitive disturbance	1/13 (7.7%)
Dizziness	1/13 (7.7%)
Dysgeusia	4/13 (30.8%)
Headache	3/13 (23.1%)
Lethargy	1/13 (7.7%)
Memory impairment	1/13 (7.7%)
Other nervous system disorders	1/13 (7.7%)
Paresthesia	1/13 (7.7%)
Peripheral sensory neuropathy	1/13 (7.7%)
Seizure	1/13 (7.7%)
Tremor	3/13 (23.1%)
Psychiatric disorders
Agitation	1/13 (7.7%)
Anxiety	2/13 (15.4%)
Confusion	2/13 (15.4%)
Depression	1/13 (7.7%)
Insomnia	2/13 (15.4%)
Other psychiatric disorders	1/13 (7.7%)
Personality change	1/13 (7.7%)
Renal and urinary disorders
Hematuria	1/13 (7.7%)
Renal calculi	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	1/13 (7.7%)
Cough	6/13 (46.2%)
Dyspnea	5/13 (38.5%)
Epistaxis	1/13 (7.7%)
Hiccups	1/13 (7.7%)
Hoarseness	1/13 (7.7%)
Hypoxia	1/13 (7.7%)
Nasal congestion	2/13 (15.4%)
Pneumonitis	1/13 (7.7%)
Voice alteration	1/13 (7.7%)
Wheezing	1/13 (7.7%)
Skin and subcutaneous tissue disorders
Alopecia	2/13 (15.4%)
Hyperhidrosis	1/13 (7.7%)
Other skin and subcutaneous tissue disorders	5/13 (38.5%)
Pruritus	1/13 (7.7%)
Rash acneiform	1/13 (7.7%)
Rash maculo-papular	3/13 (23.1%)
Urticaria	1/13 (7.7%)
Surgical and medical procedures
Other surgical and medical procedures	1/13 (7.7%)
Vascular disorders
Hematoma	1/13 (7.7%)
Hypertension	3/13 (23.1%)
Other vascular disorders	1/13 (7.7%)
Peripheral ischemia	1/13 (7.7%)
Thromboembolic event	1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.