IRB Study Number 24-308
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To determine maximum tolerated dose (MTD) or recommended combination dose of AMG 193 administered in combination with other therapies in adult subjects with metastatic or locally advanced MTAP-deleted gastrointestinal, biliary tract, or pancreatic cancers
To determine the safety profile of AMG 193 administered in combination with other therapies in adult subjects with metastatic or locally advanced MTAP-deleted gastrointestinal, biliary tract, or pancreatic cancers
Secondary Objectives
To evaluate the anti-tumor activity of AMG 193 administered in combination with other therapies in adult subjects with metastatic or locally advanced MTAP-deleted gastrointestinal, biliary tract, or pancreatic cancers
To characterize the pharmacokinetics (PK) of AMG 193 administered in combination with other therapies in adult subjects with metastatic or locally advanced MTAP-deleted gastrointestinal, biliary tract, or pancreatic cancers
Inclusion Criteria
Subprotocol A:
101 Subject has provided informed consent before initiation of any study-specific activities/procedures.
102 Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
103 Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) biliary tract cancer (intra- or extrahepatic cholangiocarcinoma or gallbladder cancer) without prior systemic therapy for metastatic or unresectable disease with the exception of 28 days of first line therapy outlined in the exclusion criteria below. Note: Participants with mixed hepatocellular carcinoma/cholangiocarcinoma may be included upon approval of the medical monitor.
104 Either archived tumor tissue (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years) or an archival block must be available (see Section 8 for more details). The archival sample must have tumor content review with at least 20% of tumor material pre-submission. Subjects without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before study treatment start on cycle 1 day 1. Subjects without sufficient archived tissue available and if a biopsy cannot be safely performed may be allowed to enroll upon agreement between the investigator and the Amgen Medical Monitor.
105 Homozygous MTAP-deletion as assessed by local or central NGS testing.
106 Able to swallow and retain PO administered study treatment and willing to record daily adherence to investigational product.
107 Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as determined by the site investigator. Lesions situated in a previously treated area by either radiotherapy, photodynamic therapy, or arterial embolization are considered measurable if progression has been shown in such lesions and they meet criteria for measurable disease per RECIST v1.1.
108 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
109 Adequate hematopoietic function per local laboratory, defined as:
absolute neutrophil count 1.5 x 109/L
platelet count 100 x 109/L
hemoglobin 9 g/dL
110 Adequate renal function per local laboratory, defined as:
estimated GFR 60 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation or Modification of Diet in Renal Disease formula.
111 Adequate liver function per local laboratory, defined as:
aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
3 X upper limit of normal (ULN) (or 5 X ULN for subjects with liver metastases)
total bilirubin < 1.5 X ULN (or < 2.0 X ULN for subjects with liver metastases, documented Gilbert’s syndrome).
Albumin ≥ 3.3 g/dL
112 Adequate coagulation parameters, defined as
prothrombin time or activated partial thromboplastin time 1.5 X ULN, and International normalized ratio (INR) 1.5 X ULN, or within expected range if on anticoagulation therapy (prophylactic or therapeutic).
113 Adequate cardiac function, defined as:
350 msec baseline QTc 470 msec (based on average of screening triplicates).
114 Minimum life expectancy of 12 weeks as per investigator judgement.
Subprotocol B
101 Subject has provided informed consent before initiation of any study-specific activities/procedures.
102 Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
103 Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas without prior systemic therapy for metastatic or unresectable disease with the exception of 28 days of first line therapy outlined in the exclusion criteria below.
104 Either archived tumor tissue (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years) or an archival block must be available (see Section 8 for more details). The archival sample must have tumor content review with at least 20% of tumor material pre-submission. Subjects without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before study treatment start on cycle 1 day 1. Subjects without sufficient archived tissue available and if a biopsy cannot be safely performed may be allowed to enroll upon agreement between the investigator and the Amgen Medical Monitor.
105 Homozygous MTAP-deletion as assessed by local or central NGS testing.
106 Able to swallow and retain PO administered study treatment and willing to record daily adherence to investigational product.
107 Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as determined by the site investigator. Lesions situated in a previously treated area by either radiotherapy, photodynamic therapy, or arterial embolization are considered measurable if progression has been shown in such lesions and they meet criteria for measurable disease per RECIST 1.1.
108 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
109 Adequate hematopoietic function per local laboratory, defined as:
absolute neutrophil count 1.5 x 109/L
platelet count 100 x 109/L
hemoglobin 9 g/dL
110 Adequate renal function per local laboratory, defined as:
Estimated GFR 50 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation or Modification of Diet in Renal Disease formula.
111 Adequate liver function per local laboratory, defined as:
aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
3 X upper limit of normal (ULN) (or 5 X ULN for subjects with liver metastases).
total bilirubin 1.5 X ULN (treatment arm A only: or 2.0 X ULN for subjects with liver metastases, documented Gilbert’s syndrome).
Albumin ≥3.3 g/dL.
112 Adequate coagulation parameters, defined as
prothrombin time or activated partial thromboplastin time 1.5 X ULN, and International normalized ratio (INR) 1.5 X ULN, or within expected range if on anticoagulation therapy (prophylactic or therapeutic).
113 Adequate cardiac function, defined as:
350 msec baseline QTc 470 msec (based on average of screening triplicates).
114 Minimum life expectancy of 12 weeks as per investigator judgement.
Exclusion Criteria
Subprotocol A
Prior/Concomitant Therapy
201 Prior systemic therapy for advanced (metastatic) or unresectable (locally advanced) biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer). In order to enable local or central prescreening NGS testing to determine MTAP-deletion, subjects that have started treatment with the standard of care first line therapy, ie, gemcitabine and cisplatin with or without anti-PD-(L)1 inhibitor, and have received their first dose within 28 days at time of signing main consent are eligible.
Neoadjuvant/adjuvant therapy:
Dose exploration: Prior neoadjuvant/adjuvant therapy is allowed without conditions.
Dose expansion: Prior neoadjuvant/adjuvant therapy is allowed if completed at least 6 months prior to diagnosis of advanced and/or unresectable disease, and if subjects did not receive gemcitabine and/or cisplatin and/or anti-PD-(L)1 antibody in the neoadjuvant/adjuvant setting. Participants who received prior neoadjuvant/adjuvant therapy with R2 postoperative pathology of the oncologic resection are excluded. NOTE: Bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.
202 Major surgery within 28 days of first dose of AMG 193
203 Prior liver directed anticancer therapy (eg, TACE, palliative surgery) for advanced unresectable biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder cancer), including investigational agents within 4 weeks prior to first dose of study treatment.
204 Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
205 Toxicities from prior anti-tumor therapy not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, with the exception of alopecia or toxicities that are stable and well controlled.
206 Subjects who experienced grade 2 or higher immune-mediated adverse events (irAEs) including those that lead to permanent discontinuation with immune oncology agents. (For immune agonists including TCE)
Exceptions: Endocrine disorders that are treated with replacement therapy.
207 Prior irradiation to > 25% of the bone marrow.
208 Radiation therapy within 28 days of first dose (or local or focal radiotherapy with palliative intend within 14 days of first dose). All radiotherapy related toxicity must have improved to ≤ grade 1 before first dose of study treatment.
209 Live vaccine therapy within 4 weeks before study drug administration.
210 Use of prescription medications that are known strong inducers or inhibitors of CYP3A4 (see Master Protocol Appendix 12 for a non-inclusive list) within 14 days or 5 half-lives (whichever is longer) before study day 1 that was not reviewed and approved by the principal investigator and the Amgen Medical Monitor.
211 Has a known sensitivity to any component of study treatment.
Disease Related
212 Untreated CNS metastatic disease regardless of symptoms. Subjects with treated CNS metastases that are radiographically and neurologically stable for ≥ 28 days and have not required corticosteroid for at least 14 days and do not require anticonvulsant prophylaxis or treatment before first dose of study treatment are eligible.
213 Subjects with leptomeningeal disease are excluded regardless of presence or absence of symptoms even if treated.
214 Ampullary cancer.
215 Patients with pleural effusions or ascites that require therapeutic drainage (eg, thoracentesis or paracentesis) at a frequency greater than one time per month.
Other Medical Conditions
216 History of other malignancy within the past 3 years, with the following exceptions:
• Adequately treated in situ cancer and precancerous lesions without evidence of disease.
Malignancy (other than in situ) treated with curative intent and with no known active disease present for ≥ 2 years before first dose and felt to be at low risk for recurrence by the treating physician. NOTE: Patients with prior or concurrent malignancy may be eligible if the risk of the malignancy interfering with either safety or efficacy endpoints is deemed to be very low in the opinion of the investigator.
217 Evidence of interstitial lung disease or active, noninfectious pneumonitis, or uncontrolled asthma.
218 Confirmed history or current autoimmune disease requiring immunosuppressive therapy.
219 History of diseases resulting in permanent immunosuppression.
220 Active infection requiring systemic therapy. Subject with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active fungal, bacterial, viral, or other infection requiring anti infectious therapy within 14 days of dosing. NOTE: Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with medical monitor. Screening for chronic infectious conditions is not required unless otherwise noted in the eligibility criteria.
221 History of arterial or venous thrombosis:
Arterial thrombosis (eg, stroke, transient ischemic attack) within 12 months of first dose.
Untreated venous thromboembolism (eg, DVT, pulmonary embolism).
Subjects on stable anti-coagulation for ≥1 month prior to first dose are eligible.
222 Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association class II), unstable angina, or cardiac arrhythmia requiring medication within 6 months of first dose of AMG 193. Patients requiring therapy must have been on stable regimen for at least 6 months.
223 Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis).
224 History or evidence of gastrointestinal disorders causing chronic nausea, vomiting, or diarrhea (defined as CTCAE grade ≥ 2).
225 Grade 2 peripheral neuropathy.
226 History of solid organ transplantation.
227 Diagnosis of Congenital Short QT Syndrome.
228 Subject will not be available for protocol-required study visits or procedures, to the best of the subject and investigator’s knowledge.
Prior/Concomitant Therapy
229 Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives since ending treatment on another investigational device or drug study(ies). Other investigational procedures and participation in observational research studies while participating in this study are excluded. Participation in observational research should be discussed with the Amgen Medical Monitor.
Diagnostic Assessments
230 Known positive test for Human Immunodeficiency Virus (HIV) with detectable viral load and without appropriate treatment.
231 Viral hepatitis infection based on the following results and/or criteria:
positive for hepatitis B surface antigen (HBsAg).
negative HBsAg and positive for hepatitis B core antibody:
hepatitis B virus DNA by polymerase chain reaction is required. Subjects with detectable hepatitis B virus DNA are ineligible.
positive Hepatitis C virus antibody (HCVAb): Hepatitis C virus RNA by PCR is required. Subjects with detectable hepatitis C virus RNA are ineligible.
Other Exclusions
232 Female subjects of childbearing potential unwilling to use protocol-specified method of contraception see (Section 11.5 during treatment and for an additional:
30 days after the last dose of AMG 193;
4 months after the last dose of pembrolizumab; and
14 months after the last dose of cisplatin.
233 Female subjects who are breastfeeding or who plan to breastfeed while on study through
30 days after the last dose of AMG 193;
4 months after the last dose of pembrolizumab;
234 Female subjects planning to become pregnant or donate eggs while on study through:
30 days after the last dose of AMG 193;
4 months after the last dose of pembrolizumab; and
14 months after the last dose of cisplatin.
235 Female subjects of childbearing potential with a positive pregnancy test assessed at Screening and/or day 1 by a highly sensitive urine or serum pregnancy test. NOTE: Patients with a positive serum pregnancy test may be considered for enrollment if in the opinion of the investigator there is convincing evidence that the test result was caused by HCG secretion by the tumor and that there is no evidence of pregnancy with other assessments such as imaging.
236 Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional:
30 days after the last dose of AMG 193; and
11 months after the last dose of cisplatin.
Refer to Section 11.5 for additional contraceptive information.
237 Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 11 months after the last dose of cisplatin.
238 Male subjects unwilling to abstain from donating sperm during treatment and for an additional:
30 days after the last dose of AMG 193; and
11 months after the last dose of cisplatin.
239 Subject has known sensitivity to any of the products or components to be administered during dosing.
240 Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge.
241 History or evidence of any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
Subprotocol B
Prior/Concomitant Therapy
201 Prior systemic therapy for advanced (metastatic) or unresectable (locally advanced) adenocarcinoma of the pancreas. In order to enable local or central prescreening NGS testing to determine MTAP deletion, subjects that have started treatment with the standard of care first line therapy, ie, gemcitabine and nab-paclitaxel (arm A) or mFOLFIRINOX (arm B) and have received their first dose within 28 days at time of signing main consent are eligible. (Exception: Part 1 [dose exploration] of arm A: a prior FOLFIRINOX-based regimen regardless of duration is allowed.)
Neoadjuvant/adjuvant therapy:
Dose exploration: Prior neoadjuvant/adjuvant therapy is allowed without conditions.
Dose expansion: Prior neoadjuvant/adjuvant therapy is allowed if completed at least 6 months prior to diagnosis of advanced and/or unresectable disease, and if subjects did not receive gemcitabine and/or nab-paclitaxel (arm 1) or any active agent of FOLFIRINOX (arm 2) in the neoadjuvant/adjuvant setting. Participants who received prior neoadjuvant/adjuvant therapy with R2 postoperative pathology of the oncologic resection are excluded. Note: Bisphosphonate or denosumab for skeletal related events per institution guideline is permitted.
202 Major surgery within 28 days of first dose of study treatment. Note: surgery to obtain a biopsy for diagnosis is allowed.
203 Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
204 Toxicities from prior anti-tumor therapy not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, with the exception of alopecia or toxicities that are stable and well controlled.
205 Prior irradiation to > 25% of the bone marrow.
206 Radiation therapy within 28 days of first dose (or local or focal radiotherapy with palliative intend within 14 days of first dose). Previously treated lesion(s) are considered measurable if progression has been shown in such lesions and they meet criteria for measurable disease per RECIST 1.1. All radiotherapy related toxicity must have improved to ≤ grade 1 before first dose of study treatment.
207 Live vaccine therapy within 4 weeks before study drug administration.
208 Use of prescription medications that are known strong inducers or inhibitors of CYP3A4 (see Master Protocol Appendix 11 for a non-inclusive list) within 14 days or 5 half-lives (whichever is longer) before study day 1 that was not reviewed and approved by the principal investigator and the Amgen Medical Monitor.
209 Has a known sensitivity to any component of study treatment.
Disease Related
210 Untreated CNS metastatic disease regardless of symptoms. Subjects with treated CNS metastases that are radiographically and neurologically stable for ≥ 28 days and have not required corticosteroid for at least 14 days and do not require anticonvulsant prophylaxis or treatment before first dose of study treatment are eligible.
211 Subjects with leptomeningeal disease are excluded regardless of presence or absence of symptoms even if treated.
212 Patients with pleural effusions or ascites that require therapeutic drainage (eg, thoracentesis or paracentesis) at a frequency greater than one time per month.
Other Medical Conditions
213 History of other malignancy within the past 3 years prior to first dose except:
Adequately treated in situ cancer and precancerous lesions without evidence of disease.
Malignancy (other than in situ) treated with curative intent and with no known active disease present for ≥ 2 years before first dose and felt to be at low risk for recurrence by the treating physician. Note: Patients with prior or concurrent malignancy may be eligible if the risk of the malignancy interfering with either safety or efficacy endpoints is deemed to be very low in the opinion of the investigator.
214 Evidence of interstitial lung disease or active, noninfectious pneumonitis, or uncontrolled asthma.
215 Confirmed history or current autoimmune disease requiring immunosuppressive therapy.
216 History of diseases resulting in permanent immunosuppression.
217 Active infection requiring systemic therapy. Subject with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active fungal, bacterial, viral, or other infection requiring anti infectious therapy within 14 days of dosing. NOTE: Simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with medical monitor. Screening for chronic infectious conditions is not required unless otherwise noted in the eligibility criteria.
218 History of arterial or untreated venous thrombosis:
Arterial thrombosis (eg, stroke, transient ischemic attack) within 12 months of first dose.
Untreated venous thromboembolism (eg, DVT, pulmonary embolism). Subjects on stable anti-coagulation ≥ 1 month prior to first dose are eligible.
219 Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association class II), unstable angina, or cardiac arrhythmia requiring medication within 6 months of first dose of AMG 193. Patients requiring therapy must have been on stable regimen for at least 6 months.
220 Gastrointestinal tract disease causing the inability to take PO medication, insufficiency on adequate pancreatic enzymes), requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis).
221 History or evidence of gastrointestinal disorders causing chronic nausea, vomiting, or diarrhea (defined as CTCAE grade ≥ 2).
222 Grade 2 peripheral neuropathy.
223 History of solid organ transplantation.
224 Diagnosis of Congenital Short QT Syndrome.
225 Known history of dihydropyrimidine dehydrogenase (DPD) deficiency.
226 Subject will not be available for protocol-required study visits or procedures, to the best of the subject and investigator’s knowledge.
227 Arm B only: Known UGT genetic polymorphisms for homozygous UGT1A1*6 or UGT1A1*28, or compound heterozygous UGT1A1*6 and UGT1A1*28.
Prior/Concomitant Therapy
228 Currently receiving treatment in another investigational device or drug study, or less than 21 days or 5 half-lives, whichever is shorter, since ending treatment on another investigational device or drug study(ies). Other investigational procedures and participation in observational research studies while participating in this study are excluded. Participation in observational research should be discussed with the Amgen Medical Monitor.
Diagnostic Assessments
229 Known positive test for Human Immunodeficiency Virus (HIV) with detectable viral load and without appropriate treatment. Note: Subjects that are adequately managed with therapies that do not interact or preclude full-dose treatment with any of the therapies in the study treatments are eligible.
230 Viral hepatitis infection based on the following results and/or criteria:
Positive for hepatitis B surface antigen (HBsAg).
Negative HBsAg and positive for hepatitis B core antibody:
Hepatitis B virus DNA by polymerase chain reaction is required. Subjects with detectable hepatitis B virus DNA are ineligible.
Positive Hepatitis C virus antibody (HCVAb): Hepatitis C virus RNA by PCR is required. Subjects with detectable hepatitis C virus RNA are ineligible.
Other Exclusions
231 Female subjects of childbearing potential unwilling to use protocol-specified method of contraception (see Section 11.5) during treatment with AMG 193, FOLFIRINOX, gemcitabine, and nab-paclitaxel and for an additional:
30 days after the last dose of AMG 193;
3 months after the last dose of fluorouracil;
9 months after the last dose of oxaliplatin; and
6 months after the last dose of irinotecan, gemcitabine, and nab-paclitaxel
232 Female subjects who are breastfeeding or who plan to breastfeed while on study through:
30 days after the last dose of AMG 193
3 months after the last dose of oxaliplatin;
7 days after the last dose of irinotecan and gemcitabine; and
2 weeks after the last dose of nab-paclitaxel
233 Female subjects planning to become pregnant or donate eggs while on study through:
30 days after the last dose of AMG 193;
3 months after the last dose of fluorouracil;
9 months after the last dose of oxaliplatin; and
6 months after the last dose of irinotecan, gemcitabine, and nab-paclitaxel
234 Female subjects of childbearing potential with a positive pregnancy test assessed at Screening and/or day 1 by a highly sensitive urine or serum pregnancy test. Note: Patients with a positive serum pregnancy test may be considered for enrollment if in the opinion of the investigator there is convincing evidence that the test result was caused by HCG secretion by the tumor and that there is no evidence of pregnancy with other assessments such as imaging.
235 Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional:
30 days after the last dose of AMG 193;
6 months after the last dose of oxaliplatin; and
3 months after the last dose of irinotecan, gemcitabine, and nab-paclitaxel.
Refer to Section 11.5 for additional contraceptive information.
236 Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 6 months after the last dose of nab-paclitaxel.
237 Male subjects unwilling to abstain from donating sperm during treatment and for an additional:
30 days after the last dose of AMG 193;
6 months after the last dose of oxaliplatin; and
3 months after the last dose of irinotecan, gemcitabine, and nab-paclitaxel
238 Subject has known sensitivity to any of the products or components to be administered during dosing.
239 Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments) to the best of the subject and investigator’s knowledge.
240 History or evidence of any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
