| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced, unresectable and/or metastatic solid tumours, which have failed with conventional treatment or for which no therapy of proven efficacy exists, or in patients who are not amenable to standard therapies and patients with diffuse large B-cell lymphoma (DLBCL) for whom there are limited or no standard treatment options available
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| E.1.1.1 | Medical condition in easily understood language |
| solid tumours or diffude large B-cell lymphoma in an advanced stage for which no standard therapy can be given |
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| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012820 |
| E.1.2 | Term | Diffuse large B-cell lymphoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010029 |
| E.1.2 | Term | Colorectal cancer NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10078295 |
| E.1.2 | Term | NUT midline carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Dose escalation part: Determine MTD for 3 schedules (A, B, C) in pats. with solid tumours, and for 2 schedules (B, C) in pats. with diffuse large B-cell lymphoma (DLBCL):
- A: continuous dosing;
- B: intermittent dosing (2 wks on, 1 wk off in 3-wk cycles);
- C: loading dose on Day 1 followed by maintenance dose for next 6 days, followed by 1 wk off treatment, repeated every 2 wks in 4-wk cycles.
Provide safety data in terms of drug-related AEs for recommendation of dose and schedule of treatment for expansion Phase Ib (only in solid tumours) of this trial, and for further trials with BI 894999. Once MTD has been determined for both schedules A and B in pats. with solid tumours, MTD will be determined as well in pats. with diffuse large B-cell lymphoma (DLBCL), using the recommended schedule for solid tumours.
Expansion phase: Collection of further safety information at the dose recommended by the DMC for Phase Ib. |
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| E.2.2 | Secondary objectives of the trial |
Secondary and further objectives in Phase Ia: Determination of the pharmacokinetic (PK) profile of BI 894999 after single and multiple dose, including the effect of food on the pharmacokinetics and assessment of anti-tumour activity.
Secondary and further objectives in Phase Ib: Increase the number of pats. with solid tumours and with evaluable PK results at the recommended Phase Ib dose (2.5 mg in Schedule B for all Schedule B cohorts or MTD loading and maintenance dose for the NUT carcinoma cohort with Schedule C if DMC decides to open this cohort), and the same as in the dose escalation part for the assessment of anti-tumour activity. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Pats. with solid tumours:
1. Confirmed diagnosis of advanced unresectable and/or metastatic, malignant solid tumour, which failed conventional treatment or for which no therapy of proven efficacy exists, or not amenable to standard therapies.
2. In Germany: Age >= 18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 at the time of screening (up to 2 in NUT carcinoma).
4. Recovery of therapy-related toxicities from previous chemotherapy, tyrosine kinase inhibitors, hormone therapy, immunotherapy, antibodies, vaccine therapy, or radiotherapy to CTCAE ≤ grade 1 (except for alopecia, peripheral sensory neuropathy grade 2).
5. Life expectancy ≥ 12 weeks after start of treatment.
6. Male and female pats. WOCBP must to use highly effective methods of birth control per ICH M3(R2).
7. Written informed consent.
8. Optional written informed consent for tumour biopsies in the escalation phase Ia.
In addition, all pats. included in the expansion Phase Ib must have:
9. one of the four diagnoses: SCLC, mCRPC, CRC or NUT carcinoma.
10. failed conventional treatments or are not amenable to standard therapies (per crit.1) that specifically include for:
a. SCLC: a platinum-based therapy (previous treatment with topotecan not mandatory);
b. mCRPC: a hormonal agent (abiraterone, enzalutamide, apalutamide) and a taxane (docetaxel, cabazitaxel);
c. CRC: fluoropyrimidine, oxaliplatin and irinotecan, bevacizumab when applicable, and an EGFR inhibitor in RAS WT mCRC.
11. measurable disease acc. to RECIST 1.1 (not needed for NUT carcinoma pats.), or acc. to PCWG3 for the mCRPC cohort (see point 5 below, specific to mCRPC pats.).
12. progressive disease within the last 6 months, acc. to RECIST 1.1 or acc. to PCWG3 for the mCRPC cohort (see point 5 below, specific to mCRPC pats.).
13. a tumour lesion accessible for biopsies (pre- and at steady state under treatment in Cycle 1, ideally from the same anatomic lesion) (except for mCRPC pats. or pats. with therapeutic INR). Biopsies are optional for NUT carcinoma pats.
14. given written informed consent for 2 tumour biopsies, one at screening and one after start of treatment, between Day 8 and Day 11 of Cycle 1 (when applicable).
In addition, all pats. in the mCRPC expansion cohort of Phase Ib must have:
1. Histologically or cytologically confirmed adenocarcinoma of the prostate.
2. Radiographic evidence of metastatic prostate cancer (stage M1 or D2). Distant metastases evaluable by bone scan, CT scan, or MRI within 28 days before the start of study treatment.
3. PSA ≥ 5 ng/mL (if no measurable disease by RECIST 1.1).
4. Prior surgical or chemical castration with a serum testosterone of <50 ng/dL (<1.7 nmol/L) by LHRH agonist or antagonist, or by abiraterone, enzalutamide or apalutamide. If actual method of castration is LHRH agonsit or antagonist, the pat. must be willing to continue use of LHRH agonist or antagonist during protocol treatment.
5. Progressive disease defined as at least one of the following:
a. Progressive measurable disease: using conventional solid tumour criteria RECIST 1.1;
b. Bone scan progression: at least two new lesions on bone scan plus a rising PSA as described in point c below;
c. Increasing PSA level: at least 2 consecutive rising PSA values over a reference value (PSA no.1) taken at least 1 week apart. A third PSA (PSA no. 3) is required to be > than PSA no. 2; if not, a fourth PSA (PSA no. 4) is required to be > to PSA no. 2.
Pats. with DLBCL:
1. Pats. with histologically confirmed DLBCL who have failed 2 or more lines of systemic therapy incl. an anti-CD20 therapy and an anthracycline, or who are not amenable to standard therapies but have an indication for therapy as per investigator’s judgement. CAR-T cells may be part of standard treatment.
2. Age >= 18 years.
3. ECOG Performance Status 0, 1 or 2 at the time of screening.
4. Measurable disease (radiated lesions do not qualify as target lesions) according to RECIL 2017 on the CT scan part of the FDG/PET-CT scan.
5. Recovery of therapy-related toxicities from previous anti-lymphoma therapy to CTCAE ≤ grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2).
6. Life expectancy of ≥ 12 weeks.
7. Male and female pats. WOCBP must use highly effective methods of birth control per ICH M3(R2).
8. Written informed consent.
9. Optional written informed consent for tumour biopsies. |
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| E.4 | Principal exclusion criteria |
Pats. with solid tumours:
1. Inability to swallow tablets.
2. Additional other serious illness , concomitant disease, e.g. active SARS-COV-2 infection confirmed by PCR test, active Hep B with positive Hep B DNA test, active Hep C with positive Hep C RNA test, HIV infection (positive HIV diagnosis), or ongoing toxicity from prior therapies considered to potentially compromise pat.’s safety in this trial.
3. History or presence of cardiovascular abnormalities deemed clinically relevant such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to study entry. LVEF less than 50% at baseline.
4. Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the last 28 days before the start of treatment with BI 894999.
5. Second malignancy currently requiring another anti-cancer therapy.
6. Absolute neutrophil count < 1,500/mm3.
7. Platelet count < 100,000/mm3.
8. Bilirubin > 1.5 mg/dL (>26 µmol/L) (except known Gilbert’s syndrome: accepted up to 2 mg/dL or up to 34.2 µmol/L in this case).
9. AST and/or ALT > 2.5 times the ULN (in the presence of liver metastases, > 5 times the ULN).
10. Serum creatinine > 1.5 mg/dL (>132 µmol/L).
11. Women who are breastfeeding, pregnant or who plan to become pregnant while in the trial.
12. Previous treatment with a BET inhibitor (allowed only for NUT carcinoma pats.).
13. Treatment with other investigational drugs or participation in another clinical interventional trial within the past 4 wks (2 wks for NUT carcinoma pats.) or within 5 times the half-life of the previous investigational drug, whichever is the shorter, before start of therapy or concomitant with this trial.
14. Systemic anti-cancer therapy within 4 wks (2 wks for NUT carcinoma pats.) or 5 times the half-life of the drug, whichever is shorter (for NMC pats., washout for monoclonal antibodies must be discussed with the Sponsor). Radiotherapy given for curative intent within 4 wks before start of therapy or concomitantly with this trial. These restrictions do not apply to LHRH agonists or antagonists, steroids (given at a stable dose in the last 4 wks) used for palliative intent , bisphosphonates, denosumab, and to palliative radiotherapy (no washout required).
15. Pats. unable to comply with the protocol.
16. Pats. who are actively abusing alcohol or drugs. Since no alcohol or drug testing is required per protocol, it is at the investigator’s discretion to determine abuse.
Pats. with DLBCL:
1. Pat. is eligible for curative salvage high dose therapy followed by stem cell transplant.
2. Primary central nervous system (CNS) lymphoma or known CNS involvement.
3. Prior allogeneic bone marrow or stem cell transplant.
4. Second malignancy currently requiring another anti-cancer therapy.
5. High-dose therapy with stem cell support <3 months prior to visit 1.
6. Inability to swallow tablets.
7. AST or ALT >2.5 x ULN (CTCAE grade 2 or higher).
8. Total bilirubin >1.5 x ULN (CTCAE grade 2 or higher).
9. Absolute neutrophil count <1,000/mm3 (without growth factor support).
10. Platelets <100,000/mm3 (without transfusions).
11. Serum creatinine 1.5 mg/dL (132 µmol/L).
12. Significant concurrent medical disease or condition which acc. to investigator’s judgement would either compromise pat. safety or interfere with the evaluation of the safety of the test drug, e.g. LVEF less than 50% at baseline, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within 6 months prior to study entry, cardiac arrhythmia requiring therapy with the exception of extra systoles or minor conduction abnormalities.
13. Chronic or ongoing infection requiring treatment at the time of enrolment or within the previous 2 weeks, e.g. active SARS-COV-2 infection confirmed by PCR test, Hep B with positive Hep B DNA test, Hep C with positive Hep C RNA test, HIV infection (positive HIV diagnosis).
14. Women who are breastfeeding, pregnant or who plan to become pregnant while in the trial.
15. Pats. who are actively abusing alcohol or drugs. Since no alcohol or drug testing is required per protocol, it is at the investigator’s discretion to determine abuse.
16. Previous treatment with a BET inhibitor.
17. Treatment with other investigational drugs or participation in another clinical interventional trial within the past 2 wks or within 5 times the half-life of the previous investigational drug, whichever is the shorter, before start of therapy or concomitant with this trial.
18. Systemic anti-DLBCL therapy within the past 2 wks or 5 times the half-life of the drug, whichever is shorter (palliative radiotherapy and agents used for palliative reasons e.g. steroids (steroids must have been given at a stable dose in the last 4 wks) and bisphosphonates are allowed).
19. Pats. unable to comply with the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- In Phase Ia: Number of pats. experiencing DLT graded according to the common terminology criteria for adverse events (CTCAE) v. 4.03, observed in the first cycle (3 wks for Schedules A and B, 4 wks for Schedule C) in order to meet the objective of assessment of the MTD of BI 894999 for each schedule in patients with solid tumours and for Schedules B and C in the DLBCL cohort.
- In Phase Ib: Number of pats. experiencing DLTs from start of treatment until end of treatment (in all cycles) as assessed at the end of each new cycle (approx. every 3 wks in Schedule B, every 4 wks in Schedule C in the NUT carcinoma cohort if this cohort is opened to recruitment), in order to determine the recommended Phase II dose and schedule selected by the DMC. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For phase Ia, the timepoint of evaluation is when the last pat. with solid tumour in the extension of MTD cohort at the chosen schedule in this phase completed the first 3 weeks of the first cycle for Schedules A and B, and 4 weeks of the first cycle for Schedule C. It is expected to be approximately after 36 months for Schedules A and B, after 12 months for Schedule C.
For phase Ib, the timepoint of evaluation is at the end of treatment of the last ongoing pat. with solid tumour, which is expected to be at approximately 36 months after start of phase Ib. |
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| E.5.2 | Secondary end point(s) |
In Phase Ia:
- Cmax and AUC0-24 after single dose, Cmax,ss and AUCτ after multiple doses of BI 894999, measured during the first cycle (3 wks for Schedules A and B, 4 wks for Schedule C).
- Number of pats. experiencing DLTs from start of treatment until end of treatment (in all cycles), assessed approx. every 3 wks in Cycle 2, for Schedules A and B, every 4 wks for Schedule C, in pats. with solid tumours, and for Schedules B and C in the DLBCL cohort.
- Objective response (OR), defined as CR or PR with tumour assessment during treatment period for each schedule. (For DLBCL pats., minor response according to RECIL 2017 is not part of an objective response.)
In Phase Ib:
- Cmax and AUC0-24 after single dose, Cmax,ss and AUCτ after multiple doses of BI 894999, observed in the first 3 wks (1st cycle) with Schedule B, in the first 4 wks (1st cycle) with Schedule C (NUT carcinoma cohort with Schedule C if DMC decides to open this cohort).
- Objective response (CR, PR) as assessed by the investigator with a tumour assessment by RECIST 1.1 every 2 cycles (6 wks if no delay for Schedule B, 8 wks if no delay for NUT carcinoma pats. treated in Schedule C) during entire treatment period.
- Progression-free survival (PFS) defined from date of start of BI 894999 to date of objective disease progression or death, whichever is earlier, with tumour assessment every 2 cycles (every 6 wks if no delays or as close as possible to the end of the 2nd of the 2 cycles of treatment if there was a delay) during treatment period.
- Best overall response, depending on the type of solid tumour, during treatment period.
- PSA response in pats. with mCRPC.
- Overall survival (OS) in NUT carcinoma pats. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK endpoints for pats. with solid tumours will be evaluated in Phase Ia at the end of the first cycle of the last entered pat. in the extension of MTD cohort at the chosen Schedule (B), approx. 36 months after start of Phase Ia.
PK endpoints for pats. with DLBCL will be evaluated in phase Ia at the end of the first cycle of the last entered pat. for MTD determination, approx. 36 months after start of DLBCL cohort.
All other endpoints - except OS status in NUT carcinoma pats. - will be evaluated at the end of the trial (end of Phase Ib) which is expected to be approx. 36 months after the start of Phase Ib. The OS status for NUT carcinoma pats. will continue until 12 months after the end of the trial. |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| Belgium |
| France |
| Germany |
| Korea, Republic of |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| LVLS: The end of trial is defined as the time when the last ongoing patient in the trial will have undergone the end of treatment visit and the follow-up visit 30 days after the end of treatment. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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