IRB Study Number 25-248
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To evaluate the efficacy of BAY 2927088 in objective response rate (ORR) as assessed by blinded independent central review (BICR)
Secondary Objectives
• To further evaluate the efficacy of BAY 2927088 on tumor growth as assessed by BICR and investigator
• To further characterize the efficacy of BAY 2927088 on tumor growth as assessed by BICR and investigator
• To evaluate the efficacy of BAY 2927088 in overall survival (OS)
• To assess the safety and tolerability of BAY 2927088
• To evaluate patient-reported outcomes (PROs) of BAY 2927088
Inclusion Criteria
Cohort 1 (Colorectal)
101 Cohort 1: Documented histologically or cytologically confirmed locally advanced, unresectable or metastatic colorectal carcinoma.
Cohort 2 (Biliary tract)
201 Cohort 2: Documented histologically or cytologically confirmed locally advanced, unresectable or metastatic biliary tract cancers, including gallbladder cancers, intrahepatic and extrahepatic cholangiocarcinoma.
Cohort 3 (Bladder)
301 Cohort 3: Documented histologically or cytologically confirmed locally advanced, unresectable or metastatic bladder and urothelial tract cancer, including renal pelvis, ureter, urinary bladder or urethra carcinoma.
Cohort 4 (Cervical)
401 Cohort 4: Documented histologically or cytologically confirmed locally advanced, unresectable or metastatic cervical cancer.
Cohort 5 (Endometrial)
501 Cohort 5: Documented histologically or cytologically confirmed locally advanced, unresectable or metastatic endometrial cancer.
Cohort 6 (Other solid tumor types)
601 Cohort 6: Documented histologically or cytologically confirmed locally advanced, unresectable or metastatic solid tumor cancer, excluding tumors specified in Cohorts 1–5 and NSCLC. Participants with sarcoma or GIST will be enrolled in Cohort 6, regardless of tumor anatomical location.
For all cohorts
Capable of providing signed informed consent as described in Appendix 1 (Section 10.1.3), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Participant signed informed consent.
Participant must be ≥18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signing the informed consent.
Patients who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. Typical standard therapies for certain tumor types are listed in Appendix 10 in Section 10.10.
Documented activating HER2 mutation as specified in Appendix 7 (Section 10.7) assessed by molecular test (see Section 8.8) in a CLIA-certified (US sites) or an equally accredited (outside of the US) local laboratory. However, participants may be included at the discretion of the investigator if the laboratory performing the assay is not CLIA or similar certified but the laboratory is locally accredited. The molecular test results should be ideally derived from tumor tissue but may be derived from plasma if tissue molecular test results are not available.
An adequate amount of tumor tissue (see Table 8–1) has to be available, either from primary or metastatic sites (see Section 8.8). If archival material is not available, a fresh tumor biopsy will satisfy this mandatory tumor tissue requirement if the procedure poses no significant risk for the participant and is performed at the discretion of the investigator. If neither an archival nor a fresh biopsy of adequate amount is available, the Sponsor should be consulted.
At least one measurable lesion that would qualify as a target lesion by RECIST 1.1 criteria (assessed by the investigator) that can be accurately measured at baseline with CT or MRI and that is suitable for accurate repeated measurements.
Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Lesions biopsied less than 2 months (4 months in case of open/surgical biopsy) before entering screening should not be selected as target lesions. Note: if it is the only potential target lesion in this participant, then the lesion should measure ≥20 mm in longest diameter.
Lesions biopsied during the screening period are not considered measurable and should not be selected as target lesions. NOTE: If a fresh biopsy is considered during screening, and the only lesion that can be biopsied is the only potential target lesion in this participant, then the lesion should measure ≥20 mm in longest diameter (or in short axis if lymph node), and the biopsy should be performed after the baseline CT/MRI scan is acquired.
ECOG performance status of ≤ 2
Participants must be able to swallow and absorb oral medication and comply with protocol procedures and scheduled visits.
Adequate bone marrow function as assessed by the following laboratory tests to be conducted within 10 days before the first dose of study intervention:
a. Hemoglobin ≥9.0 g/dL. Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within 2 weeks prior to testing.
b. Platelets ≥100 x 109 cells/L. Criteria must be met without platelet transfusion within 2 weeks prior to testing.
c. Absolute neutrophil count ≥1.5 x 109 cells/L. Criteria must be met without the use of hematopoietic growth factors (eg, granulocyte colony-stimulating factor) within 2 weeks prior to testing.
- Adequate kidney function as assessed by the following laboratory test to be conducted within 10 days before the first dose of study intervention:
a. eGFR >45 mL/min according to the CKD-EPI formula (refer to Section 10.6). Note: to convert from units of mL/minute/1.73 m2, multiply the estimated GFR by the individual’s body surface area and divide by 1.73.
- Adequate liver function as assessed by the following laboratory tests to be conducted within 10 days before the first dose of study intervention:
a. Total bilirubin ≤1.5 x ULN (or ≤3 x ULN for participants with documented Gilbert-Meulengracht Syndrome, or for participants with hyperbilirubinemia considered due to liver metastasis or biliary tract tumor involvement).
b. AST and ALT ≤2.5 x ULN (or ≤5 x ULN if due to liver involvement by tumor).
- Adequate coagulation, as assessed by the below mentioned laboratory tests as applicable, (to be conducted within 10 days before the first dose of study intervention) or on stable anticoagulation treatment as defined below:
a. INR ≤1.5 or PT ≤1.5 x ULN for participants not on anticoagulation medication.
b. aPTT ≤1.5 x ULN for participants not on anticoagulation medication.
NOTE: Participants on chronic anticoagulation therapy will be allowed to participate if the PT/INR and aPTT test results are stable at the level compatible with acceptable benefit-risk ratio at the investigator’s discretion. Participants on chronic use of direct-acting oral anticoagulants who have acceptable benefit-risk ratio at the investigator’s discretion will be allowed to participate.
Adequate cardiac function with LVEF ≥50% measured by echocardiography (recommended)/cardiac MRI/MUGA scan per institutional guidelines and normal ranges.
Negative serum pregnancy test must be obtained within 72 hours before the first dose of study intervention in WOCBP (Section 10.4 [Appendix 4])
Male and/or female who meet the requirements for contraception as follows:
a. Male participants: A male participant must agree to use contraception as detailed in Section 10.4 (Appendix 4) of this protocol during the treatment period and for at least 30 days after the last dose of study intervention, and refrain from donating sperm during this period.
b. Female participants: A female participant is eligible to participate if she is not pregnant (see Section 10.4 [Appendix 4]), not breastfeeding, and at least one of the following conditions applies:
i. Not a WOCBP as defined in Section 10.4 (Appendix 4)
ii. A WOCBP who agrees to follow the contraceptive guidance in Section 10.4 (Appendix 4) during the treatment period and for at least 30 days after the last dose of study intervention.
Exclusion Criteria
For all cohorts
Treatment with a systemic anticancer treatment ≤4 weeks or 5 half-lives, whichever is shorter, prior to the first administration of study intervention.
Primary diagnosis of NSCLC.
Prior treatment with a HER2 TKI (eg, neratinib, zongertinib, afatinib, etc).
Known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for five years since initiation of that therapy.
Exception: the following cancer types are acceptable within five years if curatively treated or under surveillance:
a. in situ cancers (eg cervix, breast, colon or skin),
b. superficial bladder cancer (Ta, Tis and T1),
c. limited-stage prostate cancer,
d. basal or squamous cancers of the skin
Received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
Any unresolved toxicity of Grade ≥2 from previous anticancer treatment, except for alopecia and skin pigmentation. Participants with chronic but stable Grade 2 toxicities may be allowed if these do not pose significant risk for the participant, nor limit participant’s compliance to study treatment and procedures, based on investigator assessment (eg, hypothyroidism from prior immunotherapy requiring thyroid replacement).
Known hypersensitivity to sevabertinib (or any drugs similar in structure or class).
Prior radiotherapy outside of the brain within 14 days of the planned start of study intervention. Participants must have recovered from all radiation-related toxicities (≤ Grade 1).
Active brain metastases (ie, new brain metastases or progressive brain metastases that have not been subjected to CNS-directed therapy since documented progression) and leptomeningeal disease (ie, positive cerebrospinal fluid cytology or unequivocal radiologic or clinical evidence of leptomeningeal involvement).
Participants with treated brain metastases that are asymptomatic at screening are eligible if all of the following criteria are met:
• There is no evidence of progression (new or enlarging brain metastases) for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
• Participants must be off or receiving low-dose of corticosteroids (≤10 mg prednisone or equivalent) for 7 days prior to the first administration of study intervention.
Note: Stable treated brain metastases allowed in this study cannot be used as target lesions and therefore should be assessed and followed as non-target metastases.
Lung-specific intercurrent clinically significant severe illness based on investigators assessment. Past medical history of: Grade ≥2 ILD; any grade drug-induced ILD; radiation pneumonitis which required steroid treatment within the last 12 months. Any Grade active pneumonitis/ILD.
Refractory nausea and vomiting, severe acute or chronic GI disorders or diseases, clinically active diverticulitis, intra-abdominal abscess, GI obstruction, ascites that requires drainage, malabsorption syndrome, serious, non-healing wound, ulcer, or bone fracture.
Known HIV, except as noted below. Participants with a history of HIV infection are eligible at the investigator’s discretion provided that:
• CD4+ T-cell (CD4+) counts are ≥350 cells/uL.
• The participant has been on established ART for at least 4 weeks prior to the start of study intervention and has an HIV viral load <400 copies/mL prior to the start of the study intervention.
• The ART being used does not contain strong inducers or inhibitors of CYP3A4, and is not anticipated to cause overlapping toxicities with study intervention (see Section 6.9.2).
• The participant has not had an opportunistic infection within the past 12 months.
- Ongoing or active infection (bacterial, fungal, or viral; eg hepatitis viral) of CTCAE (v5.0) Grade ≥3 within 28 days before the first study intervention administration.
• Any positive test result for HBV or HCV indicating the presence of virus.
• Active HBV (chronic or acute; defined as having a known positive HBsAg test at the time of screening) except for participants on anti-viral therapy for HBV with an undetectable viral load.
• Participants with past HBV infection or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible if HBV DNA is negative.
• Positive for HCVAb unless PCR is negative for HCV RNA.
Active bleeding disorders.
Use of strong CYP3A4 inhibitors and inducers from 14 days prior to the first administration of study intervention. Strong CYP3A4 inhibitors and inducers (see Section 10.5) are prohibited during the study and until the safety FU visit.
Mean resting QTcF >470 msec obtained from 3 ECGs, at screening.
History or current condition of an uncontrolled cardiovascular disease, defined as:
• Congestive heart failure New York Heart Association Class ≥2.
• Persistently uncontrolled clinically significant hypertension defined as systolic BP >150 mmHg and/or diastolic BP >100 mmHg despite optimal antihypertensive therapy.
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last three months).
• Myocardial infarction less than six months before the start of study intervention.
• Within 6 months before the start of study intervention: arterial thrombotic or embolic events, such as cerebrovascular accident (including transient ischemic attacks, ischemic stroke), or venous pulmonary embolism.
• Within 3 months before the start of study intervention: venous thrombotic events, such as deep vein thrombosis.
• Serious cardiac arrhythmias requiring treatment (eg ventricular arrhythmias) or uncontrolled cardiac arrhythmias. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec. Participants with pacemaker are eligible if the arrhythmia is controlled).
Uncontrolled, severe, intercurrent illness, including, but not limited to, hepatic, or renal disease, renal transplant or psychiatric illness/social situations that would limit compliance with study requirements.
Major surgery or significant traumatic injury (according to the investigator’s assessment) within 4 weeks prior to the first administration of study intervention or planned within 6 months after screening (eg, hip replacement).
Pregnancy or lactation.
Any history of concomitant condition or therapy that in the opinion of the investigator, would compromise the participant’s ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the test drug.
