Personalized Antibodies in Treating Patients with Metastatic Stomach or Gastroesophageal Junction Cancer
This pilot phase II trial studies personalized antibodies in treating patients with stomach or gastroesophageal junction cancer that has spread to other parts of the body. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies may block tumor growth in different ways by targeting certain cells. Testing tumor tissue for gene mutations and protein expression patterns and using drugs that target the specific profile of the tumor, may work better than standard chemotherapy in treating patients with stomach or gastroesophageal junction cancer.
Inclusion Criteria
- Histologically confirmed metastatic gastric or esophagogastric junction (type I, II, III Siewert) adenocarcinoma
- Newly-diagnosed chemo-naive or recurrent after curative-intent surgery * >= 6 months after completion of adjuvant therapy (including chemotherapy and/or radiotherapy) * No prior treatment with any targeted agent * Patients who have started first line mFOLFOX6 therapy (+/-trastuzumab for HER2 amplified tumors) may be considered for trial participation if they have received no more than 4 doses of therapy at the time of consent and screening ** These patients will be required to meet ‘next cycle’ parameters for eligibility before commencing treatment on trial rather than being required to meet parameters as indicated below which is for previously untreated metastatic/recurrent patients
- Measurable metastatic disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, * Must be amenable to ultrasound or computed tomography (CT)-guided biopsy of one metastatic lesion * Peritoneal disease as the sole site of occult metastasis or presenting as malignant ascites is acceptable if a cell block of tumor cells can be obtained showing > 20% viable tumor cells
- No currently active second malignancy
- No uncontrolled intercurrent illness or infection
- No peripheral edema >= grade 2 at baseline
- No peripheral neuropathy >= grade 2 at baseline
- No diarrhea >= grade 2 at baseline
- No autoimmune disease or chronic steroids (dose of > 10 mg/day prednisone equivalent) or other immunosuppressive medications within 7 days of randomization (for MSI-H/EBV+/TMB-high >= 15mt-Mb/PDL1+ CPS > 10% nivolumab group)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
- No cerebrovascular accident (CVA) within 6 months, no recent myocardial infarction (MI) within 6 months
- Granulocytes >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x upper limit of normal (ULN), =< 1.8 x ULN with liver metastases
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) * =< 2.5 X ULN without liver metastases * =< 5 X ULN with liver metastases
- Creatinine within normal institutional limits (< 1.5) OR creatinine clearance >= 50 mL/min/1.73m^2 (for creatinine level above normal)
- International normalized ratio (INR): =< 1.5 (patients on warfarin need to be converted to low-molecular-weight heparin [LMWH] during study participation to be eligible)
- Consent to baseline metastatic and progressive disease biopsy (of metastatic/progressing lesion) for enabling biomarker assessment and treatment assignment (at each time point – baseline, PD1, PD2, PD3) as well as for correlative studies * Consent to baseline and serial blood draws for plasma/serum/whole blood banking for correlative studies
- Ability to understand and the willingness to sign a written informed consent document and consent to the serial nature of the proposed Personalized ANtibodies for Gastro-Esophageal Adenocarcinoma (PANGEA) treatment with first, second and third line therapy as tolerated
- Ability to comply with requirements of the protocol, as assessed by the investigator by the patient signing the consent form
- If history of exposure to anthracyclines during perioperative treatment, the following cumulative doses of anthracyclines must be less than: * Epirubicin < 720 mg/m^2 * Doxorubicin or liposomal doxorubicin < 360 mg/m^2 * Mitoxantrone > 120 mg/m^2 and idarubicin > 90 mg/m^2 If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m^2 of doxorubicin
- Cardiac ejection fraction > 50% (for HER2+ patients) as assessed by echocardiogram, multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI)
- Willingness to use effective and reliable methods of contraception
- To commence second line irinotecan, bilirubin should be < 1 mg/dL; if between 1-2 mg/dL initial dose should be reduced by one dose level; if > 2 mg/dL, then irinotecan will not be used
- To commence third line docetaxel, patients must have grade 2 or less neuropathy from prior oxaliplatin treatment; also bilirubin > upper limit of normal (ULN), or AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN are not eligible for docetaxel therapy
- Patients are allowed to consent to PANGEA as long as they have received 2 months (4 doses) or less of FOLFOX (with or without fluorouracil [5FU]/leucovorin [LV] bolus) (plus trastuzumab if HER2 amplified) chemotherapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02213289.
PRIMARY OBJECTIVES:
I. To determine the safety and feasibility of obtaining baseline biopsies of metastatic disease sites (liver, lung, lymph node, peritoneum/carcinomatosis) for molecular testing, in order to proceed with the biomarker assessment and treatment assignment algorithm.
II. To determine the safety and feasibility of obtaining serial biopsies of progressing metastatic disease sites (liver, lung, lymph node, peritoneum/carcinomatosis) for molecular testing at each progression point (progressive disease [PD]1, 2, 3), in order to proceed with the biomarker assessment and treatment assignment algorithm, as assessed by rate of successful treatment category assignment.
III. To determine the median overall survival (mOS) of the combined HER2++, MET++, EGFR++/+, microsatellite instability high (MSI-H)/EBV+/tumor mutational burden (TMB)-high >= 15mt-Mb/PDL1+ combined positive score (CPS) > 10%, FGFR2+, and VEGFR2+/+ groups (N=68 total treated per intended protocol with targeted therapies) treated with their respective targeted therapies per the treatment assignment algorithm (intention to treat), with each line of cytotoxic chemotherapy (up to three lines, Biologic Beyond Progression), compared to historical controls having an aggregate mOS of approximately 12 months.
SECONDARY OBJECTIVES:
I. To determine the median overall survival (mOS) collectively of all patients undergoing tumor molecular profiling with classification into one of six predefined gastroesophageal cancer (GEC) ‘oncogenic driver’ categories (HER2++, MET++, EGFR++/+, FGFR2++, MSI-H/EBV+/TMB-High >= 15mt-Mb/PDL1+ CPS > 10%, VEGFR2++/+) with paired specific targeted therapy via the biomarker assessment and treatment algorithm, along with standard chemotherapy (up to 3 lines), compared to historical controls having an aggregate mOS of approximately 12 months.
II. To determine the median progression free survival (mPFS1) of first-line chemotherapy (modified fluorouracil, leucovorin calcium, and oxaliplatin [mFOLFOX6]) plus ‘personalized’ treatment of trastuzumab for HER2+ compared to historical controls of mPFS1 of approximately 6 months.
III. To determine the median progression free survival (mPFS1) of standard care with first-line chemotherapy (mFOLFOX6) plus ‘personalized’ treatment, compared to historical controls of mPFS1 of approximately 5 months for all patients in all five molecular categories.
IV. To determine the rate of continuing with a second-line and third-line treatment (chemotherapy backbone leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI], fluorouracil, leucovorin calcium, and docetaxel [FOLTAX]), compared to historical controls (50%, 25%); to determine the rate and type of further treatments off-protocol after completion of third line therapy.
V. To determine the mPFS2,3 of continuation of the re-targeted molecular therapy (Biologic Beyond Progression-BBP) along with the second and third line chemotherapy, compared to historical controls of mPFS2 (of approximately 4 months) and mPFS3 (of approximately 2 months) with chemotherapy alone.
VI. To determine the 6 month, 12 month, 18 month and 24 month survival rate, compared to historical controls.
VII. To determine the overall response rate (ORR) at each line of therapy (ORR1,2,3), compared to historical controls (ORR1 30%, ORR2 20%, ORR3 10%).
VIII. To determine the mPFS1+2, mPFS1+2+3.
IX. To determine the disease control rate (DCR) at each line of therapy (DCR1,2,3).
X. To determine the toxicity experienced by GEC patients treated with the combination of serial mFOLFOX6 -> FOLFIRI -> FOLTAX plus assigned biologic treatment with each line of therapy.
LABORATORY/TRANSLATIONAL EXPLORATORY CORRELATIVES OBJECTIVES:
I. To determine and refine our understanding of inter-patient GEC tumor heterogeneity by evaluating genomic and proteomic tumor profiles in all patients on trial.
II. To determine the somatic genomic changes of 315 actionable cancer-related genes (mutation, amplification, and translocation), MSI-status/IO, and 27 genes with common translocations, using targeted deep next-generation sequencing (NGS), as well as fluorescence in situ hybridization (FISH) for HER2, MET, FGFR2, EGFR, KRAS.
III. To determine the expression of known oncogenic GEC drivers including HER2, MET, FGFR2, EGFR, KRAS using i) our novel GEC-multiplexed selected reaction monitoring mass spectrometry (containing 20 oncoproteins) and ii) immunohistochemistry (IHC).
IV. To determine the relationship of these parameters to clinical outcomes including mPFS, DCR, ORR, mOS, and clinical factors including ethnicity, tumor differentiation, histology, primary anatomical location, and stage.
V. To determine and refine our understanding of intra-patient GEC tumor heterogeneity through space and time, by evaluating genomic and proteomic profiles of each tumor in all patients on trial.
VI. To determine the rate of baseline (prior to therapy) tumor molecular evolution from primary tumor to metastatic lesion (intra-patient heterogeneity through space) by comparing genomic changes (mutation, amplification, and translocation) using i) NGS (and FISH), ii) proteomic changes by GEC-plex mass spectrometry and IHC, and iii) kinase activity with PamGene iv) circulating tumor deoxyribonucleic acid (ctDNA) sequencing results.
VII. To determine the rate of tumor molecular category migration at baseline within the Biomarker and Treatment Algorithm (6 category classification) comparing primary tumor to metastatic disease.
VIII. To determine tumor molecular evolution over time (intra-patient heterogeneity through time/treatment) from baseline to first progression (PD1) and subsequent progressions (PD2, PD3) for those receiving second/third line therapy, assessing for genomic/proteomic evolution.
IX. To determine the rate of new/loss of molecular aberrations at each progression point (PD1,2,3).
X. To determine the rate of molecular category migration within the Biomarker and Treatment Algorithm at each progression point (PD1,2,3).
OUTLINE:
FIRST LINE REGIMEN: Patients receive mFOLFOX6 comprised of oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients receive the assigned biologic agent* based on the results of molecular testing. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon first progression (PD1), patients change to second line therapy as tolerated.
* BIOLOGIC AGENT: Patients receive one of the following agents based on the results of molecular testing.
HER2++: Patients receive trastuzumab IV over 30-90 minutes on day 1.
MET++: Patients receive rilotumumab IV over 30-120 minutes on day 1.
EGFR++/+: Patients receive depatuxizumab IV over 15 minutes on day 1.
FGFR2++: To be determined.
MSI-H/EBV+/TMB-High >= 15mt-Mb/PDL1+ CPS > 10%: Patients receive nivolumab IV on day 1.
VEGFR2++/+: Patients receive ramucirumab IV on day 1.
Patients will continue the selected therapy after PD1 and PD2 with the other cytotoxic backbones, FOLFIRI and FOLTAX, respectively, unless mutation status changes to one of the other 4 categories at PD1 or PD2 biopsy and molecular assessment. If molecular classification changes at either of these two time points, biologic treatment will change to the new appropriate drug for that molecular category.
SECOND LINE REGIMEN: Patients receive FOLFIRI comprised of irinotecan hydrochloride IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients receive the assigned biologic agent* based on the results of molecular testing. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Upon second progression (PD2), patients change to third line therapy as tolerated.
THIRD LINE REGIMEN: Patients receive FOLTAX comprised of docetaxel IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients receive the assigned biologic agent* based on the results of molecular testing. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 5 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorDaniel Virgil Thomas Catenacci
- Primary IDIRB14-0141
- Secondary IDsNCI-2014-02415
- ClinicalTrials.gov IDNCT02213289