| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Part A+A.1: Histologically confirmed solid tumors or NHL
Part A J-arm : Advanced solid tumors
Part B: a) DDR deficient advanced solid tumors: i) CRPC; ii) HER2- negative BC (estrogen-receptor positive, progesterone-receptor positive, or both); iii) CRC, iv) gynecological tumors (ovarian, primary peritoneal, and fallopian tube cancers, endometrial or cervical cancer). b) Patients with histologically confirmed advanced cancer and loss of ATM protein, regardless of the cancer type. |
|
| E.1.1.1 | Medical condition in easily understood language |
Part A+A.1: Histologically confirmed solid tumors or NHL
Part A J-arm : Advanced solid tumors
Part B: (a) Solid tumors, (b) Advanced cancer and loss of ATM protein |
|
| 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 | PT |
| E.1.2 | Classification code | 10028997 |
| E.1.2 | Term | Neoplasm malignant |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Part A and B: Determine the maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D), safety, tolerability, and pharmacokinetics (PK) of BAY 1895344 as single agent, in patients with advanced solid tumors and lymphomas. |
|
| E.2.2 | Secondary objectives of the trial |
| • Evaluate the response rate of BAY 1895344 in the patient population studied as single agent |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Part A J-Arm: single agent dose escalation part in Japanese patients. The objective of the J-Arm is to confirm the MTD (or RP2D) dose is safe and tolerable in Japanese patients.
Part A.1: single agent dose escalation part to evaluate a different dosing schedule of BAY 1895344 and to determine the MTD and/or RP2D for this dosing schedule.
Part A: Food effect cohort: Food effect assessment will be performed at the MTD on data from at least 6 patients with evaluable PK. If there is evaluable PK from less than 6 patients for food effect assessment, food effect will be assessed in additional patients until there is evaluable PK data from at least 6 patients. |
|
| E.3 | Principal inclusion criteria |
Part A: Patients with histologically confirmed solid tumors or NHL. Patients with tumors known to be positive for DDR defects (such as ataxia-telangiectasia mutated [ATM] deleterious mutation or low ATM expression) can be included.
J-arm: Patients with histologically confirmed solid tumors. Patients with tumors known to be positive for DDR defects (such ATM deleterious mutation or low ATM expression) can be included.
Part A.1: Patients with histologically confirmed solid tumors or NHL with ATM loss and/or ATM deleterious mutations
Part B: - Patients with DDR deficiency biomarker positive advanced solid tumors of the following histologies:
i) castration-resistant prostate cancer;
ii) HER2-negative BC that is hormone-receptor positive (estrogen-receptor positive, progesterone-receptor positive, or both) or TNBC;
iii) colorectal cancer;
iv) gynecological tumors (ovarian, primary peritoneal, and fallopian tube cancers, endometrial cancer, or cervical cancer);
v) Patients with histologically confirmed advanced cancer and loss of ATM protein by IHC (immunohistochemistry), regardless of the cancer type.
The biomarker status of patients in Part B will be evaluated before general screening and only patients with the presence of the putative biomarkers of DDR deficiency will be recruited into general screening.
The following inclusion criteria apply to ALL (dose-escalation and expansion) patients:
1. Ability to understand and the willingness to sign a written IC, obtained before any study specific procedures are performed.
2. Patients with tumors resistant or refractory to standard treatment and in which, in the opinion of the investigator, experimental treatment with BAY 1895344 may be of benefit. Furthermore, no standard therapy would confer clinical benefit.
3. Male or female patients aged ≥18 years; ≥ 20 years age for Japanese patients
4. Patients must have measurable disease (as per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] or the Lugano classification, as applicable with the exception of prostate cancer patients who must have measurable or evaluable disease per the recommendations of the PCWG3).
5. ECOG performance status of 0 to 1
6. Life expectancy of at least 12 weeks
7. Patients must have adequate bone marrow function as assessed by the following laboratory tests to be conducted within 7 (+2) days before the first dose of study drug:
a. Hemoglobin ≥9 g/dL
b. Absolute neutrophil count ≥1.5 x 10E9/L (≥1500/mm3)
c. Platelet count ≥100 x 10E9/L (≥100,000/mm3)
8. Patients must have adequate liver function as assessed by the following laboratory tests to be conducted within 7 (+2) days before the first dose of study drug:
a. Total bilirubin ≤1.5 times the upper limit of normal (ULN)
b. ALT+AST ≤3 times ULN or ≤5 times ULN for patients with malignant liver involvement
9. Patients must have adequate kidney function, as assessed by the estimated glomerular filtration rate (eGFR) >40 mL/min per 1.73 m2 within 7 (+2) days before the first dose of study drug; eGFR is to be calculated by the MDRD formula.
10. Patients must have adequate coagulation, as assessed by the following laboratory tests to be conducted within 7 (+2) days before the first dose of study drug:
a. International normalized ratio ≤1.5 and prothrombin time ≤1.5 times ULN for patients not on anticoagulation
b. Activated partial thromboplastin time ≤1.5 times ULN for patients not on anticoagulation
11. Adequate cardiac function per institutional normal measured by echocardiography or multigated acquisition (MUGA) scan
12. Women of childbearing potential must have a negative serum beta human chorionic gonadotropin pregnancy test obtained within 7 (+2) days before the start of administration of study drug.
13. Women of childbearing potential and fertile men must agree to use adequate contraception when sexually active from signing of the informed consent form for the full study until at least 6 mths after the last study drug administration. Men being treated with BAY 1895344 are advised not to father a child during and up to 6 months after treatment; prior to treatment, advice should be sought for conserving sperm. Female partners of childbearing potential from male study patients have to use adequate contraception/birth control between signing of the informed consent and 6 months after the last administration of the study drug if the male study patient is not sterilized. Male patients with female partner of reproductive potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 6 months after last study drug administration. Patients must agree to utilize 2 reliable and acceptable methods of contraception simultaneously.
18: Patients must be able to provide either samples of archival tumor tissue not older than 6 months or a fresh tumor biopsy during general screening |
|
| E.4 | Principal exclusion criteria |
The following exclusion criteria apply to ALL (dose-escalation and expansion) patients:
1. Known hypersensitivity to the study drugs or excipients of the preparations or any agent given in association with this study
2. History of cardiac disease: congestive heart failure NYHA class > II, unstable angina (angina symptoms at rest), new-onset angina (within the past 6 months before study entry), myocardial infarction within the past 6 months before study entry, or cardiac arrhythmias requiring antiarrhythmic therapy (beta blockers, calcium channel blockers, and digoxin are permitted)
3. Uncontrolled arterial hypertension despite optimal medical management
4. Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
5. Patients with known HIV infection
6. Patients who have an active HBV or HCV infection requiring treatment. Patients with chronic HBV or HCV infection are eligible at the investigator's discretion provided that the disease is stable and
sufficiently controlled under treatment.
7. Infections of CTCAE Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade >2
8. Metastatic brain, spinal or meningeal tumors unless the Patient is >3 months from definitive therapy, has a stable imaging study within 4 weeks prior to the first dose of study drug and is clinically stable with respect to the tumor at the time of study entry. Patients with asymptomatic brain metastases must not be on steroid therapy. Patients with neurological symptoms should undergo a CT / MRI scan of the brain or spinal column to exclude new or progressive brain, meningeal or spinal metastases. Patients must not be undergoing acute steroid therapy or tapering steroids (chronic steroid therapy is acceptable if the dose is stable for at least 1 month before and following screening radiographic studies).
9. Uncontrolled seizure disorder requiring therapy (e.g. strong CYP3A4 inducers such as carbamazepine and phenytoin)
10. History of organ allograft transplantation
11. Evidence or history of bleeding disorder, i.e. any hemorrhage / bleeding event of CTCAE Grade >2 within 4 weeks before the first dose of study drug
12. Serious, non-healing wound, ulcer, or bone fracture
13. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, with the exception of the following previous or concurrent cancer types:
a. Curative treatment for localized cancer completed without signs of recurrence and treatment-related toxicity and low risk of recurrence as assessed by the investigator,
b. In-situ prostate cancer, Gleason Score <7, prostate-specific Antigen <10 ng/mL (very low risk and low risk, according to therapy guidelines; active surveillance / observation is a recommended option).
14. Any clinical condition that is considered unstable or might jeopardize the safety of the patient and his / her compliance in the study
15. Inability to swallow oral medications
16. Any malabsorption condition
17. Breastfeeding. Female patients must not breastfeed during treatment and until 4 months after last study drug administration in Part A, J-arm.
18. Treatment with anticancer chemotherapy or immunotherapy during the study or within 3 weeks before the first dose of study drug. For small-molecule drugs, a period of at least 3 half-lives before the first dose of study drug is acceptable. Mitomycin C or nitrosoureas should not be given within 6 weeks before the first dose of study drug.
19. Treatment with systemic steroids (methylprednisolone dose >=10mg/day or equivalent dose).
20. Acute toxic effects (CTCAE Grade >=2) of previous anticancer chemotherapy or immunotherapy that have not yet stabilized or if significant post treatment toxicities have been observed. (Note however that toxic effects of previous anticancer therapy considered as chronic, such as chemotherapy-induced neuropathy, fatigue, alopecia, or anorexia of CTCAE Grade <2, for which further resolution is not expected, do not prevent participation in this study.)
21. Radiotherapy for target lesions during study or within 3 weeks before the first dose of study drug. Palliative radiotherapy is allowed for non-target lesions.
22. Major surgery or significant trauma within 4 weeks before the first dose of study drug
27. Use of strong CYP3A4 inhibitors and inducers from 14 days prior to first administration of study drug. Strong CYP3A4 inhibitors and inducers are prohibited during the study and until the active FU visit.
28. Narrow therapeutic index drugs that are CYP3A4 substrates are prohibited during the study and until the active FU visit.
29. Clinically relevant findings in the ECG such as a second- or third degree atrioventricular block, prolongation of the QRS complex >120 ms, or prolongation of the QTc interval (Fridericia) over 450 ms unless agreed otherwise between the investigator and the sponsor's medically responsible person |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The MTD and / or RP2D of BAY 1895344 will be assessed by the incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A, A.1, and J-arm of the study.
2. Part A, A.1, J-arm of Part A and Part B: AUC (area under the plasma concentration of BAY1895344 vs. time curve) from zero to 12 hours after single-dose (C1D1) and multiple-dose administrations (C1D10)
3. The incidence of serious and nonserious treatment-emergent adverse events (TEAEs).
4. Part A, A.1, J-arm of Part A and Part B: Cmax of BAY 1895344 in Cycle 1 after single-dose (C1D1) and multiple-dose administrations (C1D10). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 6 months, minimum: 1 cycle (=21days; in A.1 = 28 days)
2. At day 1 and day 10 of first cycle
3. Up to 66 months, minimum: 1 cycle (=21 days; in A.1 = 28 days)
4. At day 1 and day 10 of first cycle |
|
| E.5.2 | Secondary end point(s) |
1. Incidence of patients with CR, PR, SD or PD (except for patients with castration resistant prostate cancer) consistent with the RECIST 1.1 criteria.
2. Incidence of lymphoma patients with CR, PR, SD or PD consistent with the Lugano Classification.
3. Incidence of castration resistant prostate cancer patients with CR, PR, SD or PD consistent with the recommendations of the Prostate Cancer Working Group 3 (PCWG3).
CR (complete response)
PR (partial response)
SD (stable disease)
PD (progressive disease) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 66 months or until discontinuation of study, whichever comes first.
2. Up to 66 months or until discontinuation of study, whichever comes first
3. Up to 66 months or until discontinuation of study, whichever comes first. |
|
| 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 | No |
| 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) | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Canada |
| China |
| Japan |
| Singapore |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
For each participating European Union country, the end of the study consistent with the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
At the end of the study, the Long-term FU ends for any patient still on Long-term FU.
As for this study, important data will be collected after last patient last visit (LPLV) date, the end of the study as a whole will be the date when the clean database is available.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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