Clinical trial NCT00742027: Phase II Study of Oral Panobinostat in Adult Participants With Relapsed/Refractory Classical Hodgkin's Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Classical Hodgkin's Lymphoma
Keywords: Classical Hodgkin Lymphoma
Classical Hodgkin's Lymphoma
Hodgkin Lymphoma
Hodgkin's Lymphoma
Nodular sclerosing
Mixed-cellularity
Lymphocyte-rich
Lymphocyte depleted
HL
Classical HL
Refractory Hodgkin's Lymphoma
Refractory Hodgkin Lymphoma
Refractory HL
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-08-27
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Objective Response Rate (ORR) as Assessed by the Investigator Based on Cheson Response Criteria
timeFrame: From the start of the treatment of last participant up to 32 weeks
Secondary outcomes:
measure: Response Rate Based on Central Review of Computed Tomography (CT) Scan/Magnetic Resonance Imaging (MRI)
timeFrame: From start of treatment until progression/recurrence or start of a new cancer therapy (up to approximately 5 years)
measure: Time To Overall Disease Response in Responders
timeFrame: From the start of treatment up to approximately 5 years
measure: Duration of Overall Disease Response
timeFrame: From the start of treatment up to approximately 5 years
measure: Progression Free Survival (PFS)
timeFrame: From the start of treatment up to approximately 5 years
measure: The Overall Survival (OS)
timeFrame: Baseline to date of death from any cause (up to approximately 5 years)
measure: Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), And Deaths as a Measure of Safety and Tolerability of Panobinostat
timeFrame: Up to approximately 5 years
measure: Maximum Observed Concentration (Cmax) of Panobinostat
timeFrame: Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
measure: The Time to Reach Maximum Plasma Concentration (Tmax) of Panobinostat
timeFrame: Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to 28 Hours (AUC0-28) for Panobinostat
timeFrame: Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-∞) for Panobinostat
timeFrame: Cycle 1, Day 1: Pre-dose, 0.25, 1, 3, 5, 7, 24, and 28 hours post-dose
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center Dept.ofCityofHopeMedicalCtr(2)
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine/Winship Cancer Institute Dept. of Hematology (2)
state: Georgia
city: Augusta
country: United States
facility: Georgia Regents University Cancer Clinical Research Unit
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center Divisionof Hem/Onc Research(2)
state: Illinois
city: Baltimore
country: United States
facility: VA Maryland Health Care Dept.of GreenbaumCancerCent(5)
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute Hematology / Oncology
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute Div.of Hematology/Oncology
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester Hematology
state: Minnesota
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center Dept of UPenn Med Ctr (3)
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(3)
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital Cell & Gene Therapy Clinic
state: Texas
city: San Antonio
country: United States
facility: Cancer Therapy & Research Center / UT Health Science Center InstituteForDrugDevelopment(5)
state: Texas
city: Morgantown
country: United States
facility: West Virginia University/ Mary Babb Randolph Cancer Center
state: West Virginia
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Malvern
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Charleroi
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Campinas
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Dijon
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Rennes
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Göttingen
country: Germany
facility: Novartis Investigative Site
city: Köln
country: Germany
facility: Novartis Investigative Site
city: Be'er Sheva
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Udine
country: Italy
facility: Novartis Investigative Site
state: UD
city: Selangor
country: Malaysia
facility: Novartis Investigative Site
city: Auckland
country: New Zealand
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Withington
country: United Kingdom
facility: Novartis Investigative Site
state: Greater Manchester
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Chari A, Cho HJ, Dhadwal A, Morgan G, La L, Zarychta K, Catamero D, Florendo E, Stevens N, Verina D, Chan E, Leshchenko V, Lagana A, Perumal D, Mei AH, Tung K, Fukui J, Jagannath S, Parekh S. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Adv. 2017 Aug 21;1(19):1575-1583. doi: 10.1182/bloodadvances.2017007427. eCollection 2017 Aug 22.
citation: Harrison SJ, Hsu AK, Neeson P, Younes A, Sureda A, Engert A, Prince HM, Li M, Savage P, Bugarini R, Williams D, Squier M, Ritchie DS. Early thymus and activation-regulated chemokine (TARC) reduction and response following panobinostat treatment in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant. Leuk Lymphoma. 2014 May;55(5):1053-60. doi: 10.3109/10428194.2013.820287. Epub 2013 Aug 5.