| 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
|
|
| E.1.1.1 | Medical condition in easily understood language |
| solid tumours or diffuse large B-cell lymphoma in an advanced stage for which no standard therapy can be given |
|
| 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) |
|
| 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) |
|
| 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) |
|
| 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) |
|
| 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) |
|
| 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) |
|
| 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 |
The main objective of the dose escalation part is to determine the MTD for 3 schedules in patients with solid tumours (A, B and C) and in two schedules (B and C) in patients with diffuse large B-cell lymphoma (DLBCL):
- A: continuous dosing,
- B: intermittent dosing (2 weeks on, 1 week off in 3-week cycles) and
- C (loading dose on day 1 followed by a maintenance dose for the next 6 days and followed by 1 week off treatment, repeated every 2 weeks in 4-week cycles)
and provide safety data in terms of drug-related adverse events (AEs) for the recommendation of the dose and schedule of treatment for the expansion Phase Ib (only in solid tumours) and further trials with BI 894999.
In the expansion phase, the main objective lies upon collection of further safety information at the dose recommended by the data monitoring committee (DMC) for Phase Ib |
|
| E.2.2 | Secondary objectives of the trial |
Secondary and further objectives in Phase Ia are the 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.
The secondary and further objectives in Phase Ib will be to increase the number of patients 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In patients with solid tumours
1.confirmed diagnosis of advanced unresectable and/or metastatic, malignant solid tumour, which failed conventional treatment or with no therapy of proven efficacy, or not amenable to standard therapies
2.Age ≥ adult legal age for the given country when signature of informed consent (ICF). For NC patients ≥ 15 years when ICF (only adults in Germany and South Korea)
3.Oncology Group (ECOG) performance score 0 or 1 at the time of screening (up to 2 in NC)
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
6.both genders. Women of childbearing potential ready and able to use highly effective methods of birth control per ICH M3(R2)
7.Written ICF. For adolescent NC patients aged 15 to legal adult age, assent and ICF of the parents or legal guardian
8.Optional ICF for tumour biopsies in the escalation phase Ia
In addition, all patients included in the expansion Phase Ib must:
9.Have one of the four diagnoses: SCLC, mCRPC, CRC or NC
10.Have failed conventional treatments or who are not amenable to standard therapies (per criterion 1) that specifically include for:
a.SCLC: a platinum-based therapy, (previous treatment with topotecan is not mandatory)
b.mCRPC: a hormonal agent (abiraterone, enzalutamide, or apalutamide) and a taxane (docetaxel or cabazitaxel)
c.CRC: fluoropyrimidine, oxaliplatin and irinotecan, bevacizumab when applicable and an EGFR inhibitor in RAS WT mCRC.
11.Have a measurable disease according to RECIST 1.1 (for NC patients non-measurable disease only is acceptable) or according to PCWG3 for the mCRPC cohort (see point 5 below, specific to mCRPC patients)
12.Have progressive disease within the last 6 months, according to RECIST 1.1 (not needed for NC patients) or according to PCWG3 (R17-3377) for the mCRPC cohort (see point 5 below, specific to mCRPC patients).
13.Have 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 patients having only bone metastases or patients with therapeutic INR). Biopsies are optional for NC patients
14.Give written ICF for two 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 patients 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 luteinizing hormone releasing level hormone (LHRH) agonist or antagonist or by abiraterone or by enzalutamide or apalutamide. If the actual method of castration is LHRH agonist or antagonist, the patient must be willing to continue its use 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 two 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
In patients with DLBCL
1.Patients with histologically confirmed DLBCL who have failed 2 or more lines of systemic therapy including an anti-CD-20 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 when ICF
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 according to the investigator’s judgement
7.Male or female patients. Women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.
8.Written ICF which is consistent with ICH-GCP guidelines and local Legislation
9.Written ICF for tumour biopsies (optional)
|
|
| E.4 | Principal exclusion criteria |
In patients with solid tumours
1.Inability to swallow tablets
2.Additional other serious illness , concomitant disease (e.g. active infectious disease including active infection with SARS-COV-2 confirmed by a PCR test or one in the prior 6 weeks or active Hepatitis B with positive Hep B DNA test, active Hep C infection with positive Hep C RNA test and HIV infection (positive result in established HIV diagnosis assay), or ongoing toxicity from prior therapies with the potential to compromise patient’s safety in this trial
3.History or presence of cardiovascular abnormalities deemed clinically relevant by the investigator 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 requiring another anti-cancer therapy
6.Absolute neutrophil count <1500/mm3
7.Platelet count <100 000/mm3
8.Bilirubin>1.5 mg/dL (>26 µmol/L, SI unit equivalent) (except known Gilbert’s syndrome (accepted up to 2 mg/dL or up to 34.2 µmol/L in this case)
9.Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) >2.5 times the upper limit of normal (ULN) (if liver metastases, >5 times ULN)
10.Serum creatinine >1.5 mg/dL (>132 µmol/L, SI unit equivalent)
11.Women who are breastfeeding, pregnant or who plan to become pregnant during trial
12.Previous treatment with a BET inhibitor (allowed only for NC patients)
13.Treatment with other investigational drugs or participation in another interventional trial within the past 4 weeks (2 weeks for NC patients) 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 weeks (2 weeks for NC patients) or 5 times the half-life of the drug, whichever is shorter. Radiotherapy given for curative intent within the past 4 weeks 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 weeks) used for palliative intent , bisphosphonates, denosumab and to palliative radiotherapy (no wash out required)
15.Patients unable to comply with the protocol
16.Patients who are actively abusing alcohol or drugs (judgement of abuse at investigator’s discretion)
In patients with DLBCL
1.Patient 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 upper limit of normal (CTCAE grade 2 or higher)
8.Total bilirubin >1.5 x upper limit of normal (CTCAE grade 2 or higher)
9.Absolute neutrophil count <1.0 x 109/L (without growth factor support)
10.Platelets <100 x 109/L (without transfusions)
11.Serum creatinine > 1.5 mg/dL (132 µmol/L)
12.Significant concurrent medical disease or condition which according to the investigator’s judgement would either compromise patient 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 two weeks, e.g. active infection with SARS-COV-2 confirmed by PCR test or one in previous 6 weeks or active Hep B with positive Hep B DNA test, active Hep C infection with positive Hep C RNA test and HIV infection (positive result in established HIV diagnosis assay
14.Women who are breastfeeding, pregnant or who plan to become pregnant during trial
15.Patients who are actively abusing alcohol or drugs (judgement of abuse at investigator’s discretion)
16.Previous treatment with a BET inhibitor
17.Treatment with other investigational drugs or participation in another clinical interventional trial within the past two weeks or within five 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 two weeks or five times the half-life of the drug, whichever is shorter (palliative radiotherapy and agents used for palliative reasons, for example steroids and bisphosphonates, are allowed)
19.Patients unable to comply with the protocol
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-In phase Ia: Number of patients experiencing DLT graded according to the common terminology criteria for adverse events (CTCAE) v. 4.03, observed in the first cycle (3 weeks for schedules A and B, 4 weeks 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 patients experiencing DLTs from start of treatment until end of treatment (in all cycles) as assessed at the end of each new cycle (approximately every 3 weeks in schedule B, every 4 weeks for schedule C in the NC cohort if this cohort is opened to recruitment) in order to determine the recommended Phase II dose and schedule selected by the DMC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For phase Ia, the timepoint of evaluation is when the last patient with solid tumour in the extension of MTD cohort at the chosen Schedule in this phase completed the first three weeks of the first cycle for schedules A and B and four 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 patient with solid tumour, which is expected to be at approximately 36 months after start of phase Ib. |
|
| E.5.2 | Secondary end point(s) |
In phase Ia:
- Cmax and AUC0-24 after single and Cmax(,ss) and AUCτ after multiple dose of BI 894999, as measured during the first cycle (3 weeks for schedules A and B, four weeks for schedule C)
- Number of patients experiencing DLTs from start of treatment until end of treatment (in all cycles) as assessed approximately every 3 weeks after Cycle 2, for schedules A and B, every 4 weeks for schedule C in patients with solid tumours and for schedules B and C in the DLBCL cohort
- Objective Response (Complete Response (CR) and Partial Response (PR)) according to RECIST version 1.1 as assessed by the investigator throughout the entire treatment period for each schedule in patients with solid tumours and according to RECIL 2017 for schedules B and C in the DLBCL cohort (minor PR according to RECIL 2017 is not part of an objective response)
In phase Ib:
- Cmax and AUC0-24 after single and Cmax(,ss) and AUC τ after multiple dose of BI 894999, observed in the first 3 weeks (first cycle) with schedule B, in the first 4 weeks (first cycle) with schedule C (NC cohort with schedule C if the 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 weeks if no delays for schedule B, 8 weeks if no delays for NC patients treated with schedule C) during the entire treatment period. For mCRPC patients with non-measurable disease by RECIST 1.1, the assessment will be performed by bone scan plus prostate specific antigen (PSA) percentage change at the same time-points as bone scan every 4 cycles (12 weeks if no delays), as described by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3)
- Progression-free Survival (PFS) with tumour assessment every 2 cycles (6 weeks if no delays in treatment with schedule B, 8 weeks if no delays in treatment with schedule C) during the treatment period and until progression or death is reported (radiological PFS with tumour assessment by bone scan every four cycles for mCRPC patients with non-measurable disease by RECIST 1.1)
- Best overall response with an evaluation of approximately every 2 cycles (6 weeks if no delays in treatment with schedule B, 8 weeks if no delays in treatment with schedule C) during the entire treatment period (every four cycles for mCRPC patients with non-measurable disease by RECIST 1.1)
- In mCRPC patients: PSA response – defined as a decline in PSA value ≥ 50% with an evaluation every cycle during the entire treatment period
- Overall survival in patients with NC. This will be for patients in the trial after approval of protocol version 11.0 and who gave consent to this collection.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK endpoints in solid tumours will be evaluated in phase Ia at the end of the first cycle of the last entered patient in the extension of MTD cohort at the chosen Schedule between schedules A and B (schedule B chosen), approximately 36 months after start of phase Ia.
PK endpoints for patients with DLBCL will be evaluated in phase Ia at the end of the first cycle of the last entered patient for MTD determination in both schedules B and C, approximately 36 months after start of DLBCL cohort.
All other endpoints except the overall survival (OS) status in NC patients will be evaluated at the end of the trial (end of phase Ib) which is expected to be approximately 36 months after the start of phase Ib. The OS status for the NC patients will continue until 12 months after the end of trial |
|
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 |
| Korea, Republic of |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Spain |
|
| 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
|
| 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. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 24 |
| 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 |
Print
