First-in-human study of ATR inhibitor BAY 1895344 in patients with advanced solid tumors and lymphomas.

Phase 1

• Conditions: Part A: Histologically confirmed solid tumors and lymphomas, J-arm : Advanced solid tumorsPart B: a) DDR defects putative biomarker-positive advanced solid tumors: i) CRPC; ii) lung cancer, including adenocarcinoma, squamous carcinoma, or small cell lung cancer; iii) colorectal cancer; iv) gynecological tumors. b) Advanced mantle cell lymphoma. Diffuse large B cell lymphoma. Part C: CRPC with symptomatic confirmed bone metastases and no known visceral metastatic disease.; MedDRA version: 20.0Level: PTClassification code 10028997Term: Neoplasm malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2016-004484-39-FR
• Lead Sponsor: Bayer AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-02-13
• Last Update Posted: 23 July 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 320

Inclusion Criteria

Part A - single-agent dose-escalation part: 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 - single-agent dose-escalation part: Patients with histologically confirmed solid tumors. 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.
Part B - single-agent expansion part: - Patients with DDR deficiency biomarker positive advanced solid tumors of the following histologies:
i) castration-resistant prostate cancer (CRPC);
ii) lung cancer, including adenocarcinoma, squamous carcinoma, or small cell lung cancer (SCLC);
iii) colorectal cancer (CRC) and
iv) gynecological tumors (ovarian cancer, endometrial cancer, or cervical cancer).
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.
- Patients with histologically confirmed MCL. Patients with diffuse large B cell lymphoma (DLBCL) known to be positive for DDR defects (such as ATM deleterious mutation or low ATM expression).
Part C - combination with Xofigo:
CRPC with symptomatic confirmed bone metastases and no known visceral metastatic disease
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 evaluable or measurable disease (as per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1], the Lugano classification, or the recommendations of the PCWG3 as applicable).
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 >=8.5 g/dL (Part A, J-arm, B); >=9.0 g/dL (Part C)
b. Absolute neutrophil count (ANC) >=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 (INR) <=1.5 and prothrombin time (PT) <=1.5 times ULN for patients not on anticoagulatio

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. Symptomatic metastatic brain 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 to exclude new or progressive brain metastases.
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
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 considere

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified