| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients With Relapsed/Refractory MYC-Altered Diffuse Large B-Cell Lymphoma |
|
| 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 | 19.0 |
| 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 | 19.0 |
| 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 monotherapy and in combination with rituximab (R-907), as measured by the objective response rate (ORR) in subjects with relapsed and/or refractory (RR) diffuse large B-cell lymphoma (DLBCL) with MYC altered disease |
|
| E.2.2 | Secondary objectives of the trial |
·To evaluate PFS, median PFS, and PFS at 6 months (PFS6).
·To evaluate OS.
·To evaluate the duration of response (DOR).
·To evaluate the incidence and severity of AEs, serious adverse events (SAEs), and other safety parameters in subjects receiving CUDC-907 and R-907.
·To characterize the pharmacokinetics (PK) of CUDC-907 alone and when administered in combination with rituximab.
|
|
| 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 the treatment of DLBCL and ineligible for ASCT (or failed) autologous or allogeneic stem cell transplant (salvage therapy, conditioning therapy and maintenance with transplant will be considered one prior treatment).
3. Histopathologically confirmed diagnosis of RR DLBCL:
· Diagnosis of follicular lymphoma transformed to DLBCL (aka t-FL DLBCL) is allowed. Other B-cell lymphomas including DLBCL unclassified and Burkitt’s lymphoma are not eligible.
4. Histopathologically confirmed MYC-altered status by archival tumor samples (collected within 1 year of study entry and/or within 1 line of prior therapy, whichever is closer to the time of study entry) or fresh tumor samples by one of the following:
· Local or central laboratory (if local testing is not available) FISH results of MYC translocation, or
· Local or central laboratory (if local testing is not available) IHC results with expression of MYC ≥ 40%, and/or gene copy number gain by FISH
5. Confirmed availability of viable tissue (defined as archival tumor tissue collected within 1 year of study entry and/or within 1 line of prior therapy, whichever is closer to the time of study entry, or fresh tumor samples) for central laboratory FISH and IHC testing and review prior to study dosing.
6.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. Baseline FDG-PET scans, if used, must demonstrate positive lesions compatible with CT-defined anatomical tumor sites.
7. Presence of RR disease per Revised Response Criteria for Malignant Lymphoma (Cheson et al, 2007) after receipt of at least 2 but no more than 4 prior lines of treatment for DLBCL, at least one of which included an anthracycline.
· Relapsed disease is defined by DLBCL confirmed by excisional/incisional biopsy (preferred) or fine needle aspiration (FNA) or core needle biopsy (CNB) after a complete response (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) partial response (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.
8.Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
9.Recovery to Grade 1 or baseline of any toxicity due to prior anticancer therapies (excluding alopecia).
10.Absolute neutrophil count ≥ 1,000/µL; platelets ≥ 75,000/µL; creatinine ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × ULN; total bilirubin ≤ 1.5 × ULN. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to screening complete blood count (CBC) and Cycle 1, Day 1 treatment.
11. Women of childbearing potential must have a negative serum or urine pregnancy test (not applicable after bilateral oophorectomy)
12. 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 and 365 days following the last study treatment for subjects receiving CUDC-907 and R-907, respectively. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence. Acceptable methods of contraception are described in Table 3.
13.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. Known lymphomatous involvement of the central nervous system (CNS) unless deemed clear of malignant involvement by cytologic examination of cerebrospinal fluid. Subjects with known bone marrow involvement will require prior chemoprophylaxis per local standard to prevent CNS relapse.
3. Known allergy or hypersensitivity to phosphatidylinositol 3 kinase (PI3K) inhibitors or any component of the formulations used in this study. Prior treatment with an HDAC inhibitor is not allowed (whereas prior treatment with a PI3K inhibitor is allowed). Hypersensitivity reaction to rituximab ≥ Grade 3 (does not apply to subjects enrolled into CUDC-907 monotherapy groups).
4. Cytotoxic anticancer therapy (e.g., alkylating agents, anti-metabolites, purine analogues) within 2 weeks of study entry.
5.Radiotherapy 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:
·Glucocorticoids to reduce the potential for infusion reactions to rituximab are allowed per institutional guidelines.
· Doses ≤ 1 mg/kg/day prednisolone or equivalent glucocorticoid and inhalational therapies for mild chronic obstructive pulmonary disease (COPD) or asthma are allowed.
·Replacement dosing of steroids (defined as < 30 mg/day hydrocortisone or the 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.
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 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 pharmacokinetics 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| 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) |
• PFS, median PFS, and PFS6
• DOR
• OS
|
|
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 |
| France |
| Germany |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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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