Phase II Study of Oral Panobinostat in Adult Participants With Relapsed/Refractory Classical Hodgkin's Lymphoma

Classical Hodgkin's Lymphoma Clinical Trial

Official title:

A Phase II Study of Oral Panobinostat in Adult Patients With Relapsed/Refractory Classical Hodgkins Lymphoma After High-dose Chemotherapy With Autologous Stem Cell Transplant

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00742027
• Other study ID #: CLBH589E2214
• Secondary ID: 2008-003016-35
• Status: Completed
• Phase: Phase 2
• Start date: September 16, 2008
• Est. completion date: August 12, 2013

Study information

• Verified date: July 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluated the efficacy of oral panobinostat in participants with refractory/relapsed classical Hodgkins lymphoma (HL) who have received prior treatment with high dose chemotherapy and autologous stem cell transplant. Safety of panobinostat also was assessed. Other markers that may correlate with efficacy or safety were explored.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 129
• Est. completion date: August 12, 2013
• Est. primary completion date: August 12, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Participant age is = 18 years.

2. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of = 2.

3. Participant has a history of classical Hodgkin's Lymphoma (HL) (i.e. Nodular sclerosing, Mixed-cellularity, Lymphocyte-rich, Lymphocyte depleted).

4. Participant has progressive disease after receiving high dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT).

Note: If last therapy was = 18 months ago, then biopsy should be performed to confirm diagnosis.

Note: Participant should have received = 5 prior systemic treatment regimens (See Post-text supplement 2 for definitions and examples).

Note: Participant will be allowed on study who have also received an allogeneic hematopoietic stem cell transplant, however this therapy alone is not sufficient for inclusion into this study.

5. Participant has at least one site of measurable nodal disease at baseline = 2.0 centimeter (cm) in the longest transverse diameter and clearly measurable in at least two perpendicular dimensions, as determined by computed tomography (CT) scan (magnetic resonance imaging [MRI] is allowed only if CT scan can not be performed).

Note: Participant with bone marrow involvement are eligible, but this criteria alone should not be used for disease measurement.

6. Participant has the following laboratory values (labs may be repeated, if needed, to obtain acceptable values before screen fail):

• Absolute neutrophil count (ANC) = 1.5 x 10^9/liter (L) [International System of Units {SI} units 1.5 x 10^9/L].

• Platelet count = 75 x 10^9/L.

• Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution.

Note: Potassium, calcium, magnesium, sodium, and/or phosphorus supplements may be given to correct values that are < lower limits of normal (LLN). Post-correction values must not be deemed to be a clinically significant abnormality prior to participant being dosed.

• Serum creatinine = 1.5 x upper limits of normal (ULN).

• Serum bilirubin = 1.5 x ULN (or = 3.0 x ULN, if participant has Gilbert syndrome).

• Aspartate transaminase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) and/or alanine transaminase (ALT)/ serum glutamic pyruvic transaminase (SGPT) = 2.5 x ULN or = 5.0 x ULN if the transaminase elevation is due to disease involvement.

7. Clinically euthyroid. Note: Participants are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.

8. Written informed consent was obtained from the participant prior to any study-specific screening procedures.

9. Participant has the ability to swallow capsules or tablets.

Exclusion Criteria:

1. Participant has a history of prior treatment with a deacetylase (DAC) inhibitor including panobinostat.

2. Participant will need valproic acid for any medical condition during the study or within 5 days prior to the first panobinostat treatment.

3. Participant has been treated with monoclonal antibody therapy (e.g., rituximab or anti CD-30 antibody, etc.) within 4 weeks of start of study treatment.

4. Participant has received chemotherapy or any investigational drug or undergone major surgery = 2 weeks prior to starting study drug or whose side effects of such therapy have not resolved to = grade 1.

5. Participant has been treated with > 5 prior systemic lines of treatment (see Post-text supplement 2 for definitions and examples).

6. Participant has received prior radiation therapy = 4 weeks or limited field radiotherapy = 2 weeks prior to start of study treatment or whose side effects of such therapy have not resolved to = grade 1.

7. Participant is using any anti-cancer therapy concomitantly.

8. Participant treated with allogeneic hematopoietic stem cell transplant who is currently on or has received immunosuppressive therapy within 90 days prior to start of screening and/or have = Grade 2 graft versus host disease (GvHD).

9. Participant has a history of another primary malignancy = 3 years before study entry, with the exception of non-melanoma skin cancer, and carcinoma in situ of uterine cervix.

10. Participant has a history of central nervous system (CNS) involvement with lymphoma.

11. Participant has impaired cardiac function including any of the following:

• Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (<50 beats per minute [bpm]), QT interval (QTcF) > 450 milliseconds (msec) on screening electrocardiography (ECG), or right bundle branch block + left anterior hemiblock (bifascicular block).

• Presence of atrial fibrillation (ventricular heart rate >100 bpm).

• Previous history angina pectoris or acute myocardial infarction (MI) within 6 months.

• Congestive heart failure (New York Heart Association functional classification III-IV) or baseline multigated acquisition (MUGA)/Echo shows left ventricular ejection fraction (LVEF) < 45%.

12. Participant has any other clinically significant heart disease (e.g., uncontrolled hypertension).

13. Participant has an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection).

14. Participant has unresolved diarrhea = grade 2.

15. Participant has any other concurrent severe and/or uncontrolled medical condition(s) (e.g., uncontrolled diabetes mellitus, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol.

16. Participant has a known history of human immunodeficiency virus (HIV) seropositivity (screening HIV testing is not required).

17. Participant is using medications that have a relative risk of prolonging the QT interval or of inducing Torsade de Pointes, where such treatment cannot be discontinued or switched to a different medication prior to starting study drug.

18. Participant is a woman who is pregnant or breast feeding, or a women of childbearing potential (WOCBP) not willing to use a double method of contraception during the study through 3 months after the end of treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). WOCBP must have a negative serum pregnancy test at baseline.

19. Male participant whose sexual partner(s) are WOCBP who are not willing to use a double method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.

Participants with any of the following contraindications to positron emission tomography (PET) are excluded from the [18F]- fludeoxyglucose (FDG) PET study (only applicable for centers participating in the PET study):

20. Fasting blood glucose above 200 milligrams per deciliter (mg/dL), at time of PET scan.

21. Inability to lay down for 60 minutes or has a history of claustrophobia.

22. Participant not at a participating center.

Related Conditions & MeSH terms

• Classical Hodgkin's Lymphoma
• Hodgkin Disease
• Lymphoma

Intervention

Drug:
• Panobinostat
Panobinostat hard gelatin capsules.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Malvern	Victoria
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Lyon Cedex
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Rennes
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Göttingen
Germany	Novartis Investigative Site	Köln
Israel	Novartis Investigative Site	Be'er Sheva
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Rozzano	MI
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Udine	UD
Malaysia	Novartis Investigative Site	Selangor
New Zealand	Novartis Investigative Site	Auckland
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Cataluña
Spain	Novartis Investigative Site	Madrid
United Kingdom	Novartis Investigative Site	Southampton
United Kingdom	Novartis Investigative Site	Withington	Greater Manchester
United States	Emory University School of Medicine/Winship Cancer Institute Dept. of Hematology (2)	Atlanta	Georgia
United States	Georgia Regents University Cancer Clinical Research Unit	Augusta	Georgia
United States	VA Maryland Health Care Dept.of GreenbaumCancerCent(5)	Baltimore	Maryland
United States	Dana Farber Cancer Institute Hematology / Oncology	Boston	Massachusetts
United States	Rush University Medical Center Divisionof Hem/Onc Research(2)	Chicago	Illinois
United States	Karmanos Cancer Institute Div.of Hematology/Oncology	Detroit	Michigan
United States	City of Hope National Medical Center Dept.ofCityofHopeMedicalCtr(2)	Duarte	California
United States	The Methodist Hospital Cell & Gene Therapy Clinic	Houston	Texas
United States	University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(3)	Houston	Texas
United States	West Virginia University/ Mary Babb Randolph Cancer Center	Morgantown	West Virginia
United States	University of Pennsylvania Medical Center Dept of UPenn Med Ctr (3)	Philadelphia	Pennsylvania
United States	Mayo Clinic - Rochester Hematology	Rochester	Minnesota
United States	Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(5)	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  France,  Germany,  Israel,  Italy,  Malaysia,  New Zealand,  Singapore,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) as Assessed by the Investigator Based on Cheson Response Criteria	ORR was number of participants with best overall disease response of complete response(CR)/partial response(PR).Best overall disease response was best disease response recorded from start of treatment until disease progression/recurrence.CR=complete normalization of all index nodal,extranodal lesions,complete disappearance of all extranodal lesions.PR=50% decrease in SPD for up to 6 identified dominant lesions (splenic,hepatic nodules) from baseline.Stable=neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease (PD), reference smallest sum diameters while on study.Progression=50% increase in sum of longest diameter of all target lesions,from smallest sum of longest diameter of all target lesions recorded at or after baseline/a new lesion/progression of non-target lesions.Unknown is progression not documented,one/more of index lesions not assessed or have been assessed using a different method than baseline at the time of radiologic evaluation.	From the start of the treatment of last participant up to 32 weeks
Secondary	Response Rate Based on Central Review of Computed Tomography (CT) Scan/Magnetic Resonance Imaging (MRI)	Best overall radiological response (CT/MRI) was recorded from start of treatment until progression/ recurrence. CR=complete normalization of all index nodal,extranodal lesions,complete disappearance of all extranodal lesions.PR=50% decrease in SPD for up to 6 identified dominant lesions (splenic,hepatic nodules) from baseline.Stable=neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease (PD), reference smallest sum diameters while on study.Progression=50% increase in sum of longest diameter of all target lesions,from smallest sum of longest diameter of all target lesions recorded at or after baseline/a new lesion/progression of non-target lesions.Unknown is progression not documented,one/more of index lesions not assessed or have been assessed using a different method than baseline at the time of radiologic evaluation.	From start of treatment until progression/recurrence or start of a new cancer therapy (up to approximately 5 years)
Secondary	Time To Overall Disease Response in Responders	Time to overall disease response (CR or PR) was defined as the time from the date of randomization/start of treatment to the date of first documented disease response (PR or CR). Per Cheson response criteria, CR= is a complete normalization of all index nodal and extranodal lesions and complete disappearance of all extranodal lesions. PR= is a 50% decrease in the SPD for up to 6 identified dominant lesions, including splenic and hepatic nodules from baseline. Participants were considered responders if they had a partial or complete response to a treatment while in the study as per Investigator's assessment.	From the start of treatment up to approximately 5 years
Secondary	Duration of Overall Disease Response	Duration of overall response (CR or PR) was defined as the time from the date of first documented disease response (CR or PR) to the date of first documented progression or death due to lymphoma. Per Cheson response criteria, CR= is a complete normalization of all index nodal and extranodal lesions and complete disappearance of all extranodal lesions. PR= is a 50% decrease in the SPD for up to 6 identified dominant lesions, including splenic and hepatic nodules from baseline. Participants were considered responders if they had a partial or complete response to a treatment while in the study.	From the start of treatment up to approximately 5 years
Secondary	Progression Free Survival (PFS)	Progression-free survival (PFS) was defined as the time from the date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a participant has not had an event, progression-free survival was censored at the date of the last adequate assessment.	From the start of treatment up to approximately 5 years
Secondary	The Overall Survival (OS)	OS was the duration from date of randomization to date of death from any cause. If a participant has not had an event, overall survival was censored at the date of the last adequate assessment.	Baseline to date of death from any cause (up to approximately 5 years)
Secondary	Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), And Deaths as a Measure of Safety and Tolerability of Panobinostat	An AE is the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring after signing the informed consent even if the event is not considered to be related to the study drug(s). SAEs are AEs leading to death, are life-threatening, require hospitalizations or prolongation of hospitalizations, represent an innate malformation or a congenital abnormality.	Up to approximately 5 years
Secondary	Maximum Observed Concentration (Cmax) of Panobinostat		Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
Secondary	The Time to Reach Maximum Plasma Concentration (Tmax) of Panobinostat		Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to 28 Hours (AUC0-28) for Panobinostat		Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-8) for Panobinostat		Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose