| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma
including patients with MYC alterations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse Large B-Cell Lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012821 |
| E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012822 |
| E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of CUDC-907 as measured by the objective
response rate (ORR) in Group B subjects with relapsed and/or refractory (RR) diffuse large B-cell lymphoma (DLBCL) with MYC altered disease by immunohistochemistry (IHC) |
|
| E.2.2 | Secondary objectives of the trial |
· To evaluate ORR (local determination) in Group B subjects.
· To evaluate PFS, median PFS, and PFS at 6 months (PFS6) in Group B
subjects.
· To evaluate OS in Group B subjects.
· To evaluate the disease control rate (DCR) and the duration of response (DOR) in Group B subjects
· To evaluate ORR in Group A and C subjects.
· To evaluate the incidence and severity of AEs, serious adverse events
(SAEs), and other safety parameters in subjects receiving CUDC-907.
· To characterize the pharmacokinetics (PK) of CUDC-907. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. At least two but no more than 4 prior lines of therapy for treatment of de novo DLBCL and ineligible for (or failed) autologous or allogeneic SCT (salvage therapy, conditioning therapy and maintenance with transplant will be considered one prior treatment).
3. Histopathologically confirmed diagnosis of one of the following:
- RR DLBCL per the 2008 WHO classification of hematopoietic and
lymphoid tumors
- HGBL, with MYC and BCL2 and/or BCL6 rearrangements or DLBCL, NOS per the 2016 revision of the WHO classification of lymphoid neoplasms.
- Diagnosis of t-FL DLBCL is allowed. However, other B-cell lymphomas
including B-cell lymphoma/DLBCL unclassifiable with features
intermediate between DLBCL, per the 2008 WHO classification, HGBL,
NOS per the 2016 WHO classification, and Burkitt are not eligible.
4. Confirmed availability of viable tissue (defined as most recent
available archival tumor tissue available or fresh tumor samples) for
central laboratory FISH and IHC testing and review prior to study
dosing. Previously decalcified samples are not appropriate for FISH
testing. Therefore bone marrow samples are not acceptable. For subjects who enter the study with unconfirmed MYC-altered disease, fresh tumor samples are preferred.
5. CT scan showing at least 1 or more clearly demarcated lymph node(s)
with a long axis > 1.5 cm and short axis > 1.0 cm or 1 clearly demarcated extranodal lesion(s) with a long axis >1.0 cm and short axis
>1.0 cm. All lesions must have a maximum diameter of < 10 cm.
Baseline FDG-PET scans, if used, must demonstrate positive lesions
compatible with CT-defined anatomical tumor sites.
6. Presence of RR disease per Revised Response Criteria for Malignant
Lymphoma.
· Relapsed disease is defined by DLBCL confirmed by
excisional/incisional biopsy (preferred) or fine needle aspiration
(FNA) or core needle biopsy (CNB) after a CR or unconfirmed complete
response (CRu).
- For relapse during first-line treatment, biopsy/FNA reconfirmation
of the lymphoma is recommended but not mandatory.
· Refractory disease is defined by (a) PD during first-line treatment, (b)
stable disease (SD) after ≥ 3 cycles of first-line treatment, or (c) PR
after ≥ 6 cycles of first line treatment, or for stage II disease, ≥ 3 cycles
of treatment and definitive involved field radiotherapy. -
- For sustained PR after first-line treatment, confirmation biopsy for
DLBCL is preferred. An FNA may be acceptable, but if inappropriate (e.g. due to biopsy inaccessibility), the Sponsor may determine eligibility
following review of imaging results and disease history.
- For SD or PD after first-line treatment, reconfirmation of DLBCL by
biopsy (preferred) or FNA is recommended but not mandatory.
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤
1.
8. Recovery to Grade 1 or baseline of any toxicity due to prior anticancer therapies (excluding alopecia).
9. Absolute neutrophil count (ANC) ≥ 1,000/μL; platelets ≥ 75,000/μL;
creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine
clearance ≥ 50 mL/minute as determined by Cockcroft-Gault (using
actual body weight) or by 24-hour urine collection measurements of
creatinine; aspartate aminotransferase (AST) and/or alanine
aminotransferase (ALT) ≤ 2.5 × ULN; total bilirubin ≤ 1.5 × ULN or ≤ 3
ULN for patients with documented Gilbert's syndrome. Platelet
transfusions and administration of granulocyte colony-stimulating
factors to help patients meet eligibility criteria are not allowed within 1
week prior to screening complete blood count (CBC) and Cycle 1, Day 1
treatment.
10. Women of childbearing potential must have a negative serum or
urine pregnancy test (not applicable after bilateral oophorectomy).
11. Men and women of childbearing potential and their partners must
agree to use adequate birth control throughout their participation in the study and for 30 days following the last study treatment. Adequate
contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
12. In the Investigator's judgement, able to provide written informed
consent and follow protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Known primary mediastinal, ocular, epidural, testicular or breast
DLBCL.
2. Patients must not have active CNS involvement of their malignancy.
Patients with prior brain metastases are permitted, but must have
completed treatment and have no evidence of active CNS disease (clear
cerebrospinal fluid [CSF]) for at least 4 weeks prior to the first dose of
CUDC-907. Intrathecal chemoprophylaxis to prevent the emergence or
recurrence of lymphoma in the CNS is permitted on study and may be
administered per institutional guidelines.
3. Known allergy or hypersensitivity to PI3K inhibitors or any component
of the formulations used in this study.
4. Cytotoxic anticancer therapy (e.g., alkylating agents, anti-metabolites, purine analogues) or any other systemic anticancer therapy within 2 weeks of study entry.
5. Radiotherapy delivered to non-target lesions within one week prior to starting study treatment or delivered to target lesions that will be
followed on the study (note: prior sites of radiation will be recorded).
6. Treatment with experimental therapy within 5 terminal half-lives
(t1/2) or 4 weeks prior to enrollment, whichever is longer.
7. Current or planned glucocorticoid therapy, with the following
exceptions :
- Doses ≤ 10 mg/day prednisolone or equivalent is allowed, provided
that the steroid dose has been stable or tapering for at least 14 days
prior to the first dose of CUDC-907.
- Inhaled, intranasal, intraarticular, and topical steroids are permitted
8. Graft versus host disease following transplant within 100 days prior to study treatment.
9. Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study treatment.
10. Diabetes mellitus that is not controlled with medication.
11. Serious infection requiring intravenous antibiotic therapy within 14
days prior to study treatment.
12. Uncontrolled or severe cardiovascular disease, including myocardial
infarction, unstable angina, or atrial fibrillation (AFib) within 6 months
prior to study treatment, New York Heart Association (NYHA) Class II or
greater congestive heart failure, serious arrhythmias requiring
medication for treatment, clinically significant pericardial disease,
cardiac amyloidosis, or QTc with Fridericia's (QTcF) correction that is
unmeasurable or ≥ 480 msec on screening electtrocardiogram ECG
(Note: for QTcF ≥ 480 sec on the screening ECG, the ECG may be
repeated twice at least 24 hours apart; the mean QTcF from the three
screening ECGs must be < 480 msec in order to meet eligibility for trial
participation).
13. Gastrointestinal disease or disorder that could interfere with the
swallowing, oral absorption, or tolerance of CUDC-907. This includes
uncontrolled diarrhea (> 1 watery stool/day), major abdominal surgery,
significant bowel obstruction and/or gastrointestinal diseases that could
alter the assessment of PK or safety, including but not limited to:
irritable bowel syndrome, ulcerative colitis, Crohn's disease and
hemorrhagic coloproctitis.
14. History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 1 year prior to the first dose of study drug, provided it is deemed to be at low risk for recurrence by the treating physician.
- These conditions include but are not limited to non-melanoma skin
cancer, carcinoma in situ, (including superficial bladder cancer), cervical
intraepithelial neoplasia and organ-confined prostate cancer.
15. Known infection with human immunodeficiency virus (HIV).
16. Known active or chronic hepatitis B virus (HBV) or hepatitis C virus
(HCV) infection.
- Regardless of hepatitis B surface antigen (HBsAg) status, if hepatitis B
core antibody (HBcAb) is positive, then HB DNA testing will be
performed and if positive the patient will be excluded.
- Regardless of hepatitis RNA level, patients who are positive for
hepatitis C antibody (anti HCV) will be permitted to enroll provided that
they meet all eligibility criteria and are without evidence of cirrhosis.
Patients diagnosed with HCV < 6 months prior to enrollment will be
considered to have acute HCV and excluded unless viral load is
undetectable.
17. Pregnant or breast-feeding women.
18. Unstable or clinically significant concurrent medical condition that
would, in the opinion of the Investigator, jeopardize patient safety
and/or compliance with the protocol.
19. Active cytomegalovirus (CMV) infection as defined per local
standards by CMV PCR, presence of CMV antigenemia, or evidence of any invasive CMV end organ disease (e.g., CMV colitis), or any prior history of CMV organ infection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR (central determination) in Group B subjects |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
every 12 weeks during the first 6 months, then every 24 weeks until PD
or death, or up to 2 years, whichever occurs first. After that, disease
assessments may be performed as clinically indicated. Overall survival
may be checked by phone every 3 months |
|
| E.5.2 | Secondary end point(s) |
• ORR (local determination) in Group B subjects
• PFS, median PFS, and PFS6 (central and local determination) in Group
B subjects
• OS in Group B subjects
• DCR and DOR (central and local determination) in Group B subjects
• ORR (central and local determination) in Group A and C subjects. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
every 12 weeks during the first 6 months, then every 24 weeks until PD
or death, or up to 2 years, whichever occurs first. After that, disease
assessments may be performed as clinically indicated. Overall survival
may be checked by phone every 3 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Hungary |
| Korea, Republic of |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last patient undergoing the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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