Savolitinib in Treating Patients With MET Amplified Metastatic or Unresectable Colorectal Cancer

This phase II trial studies how well savolitinib works in treating patients with MET amplified colorectal cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Savolitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To estimate the objective response rate (ORR) of savolitinib in patients with MET amplified metastatic colorectal cancer (CRC).

SECONDARY OBJECTIVES:

I. To describe the clinical activity (duration of response, progression free survival \[PFS\]) of savolitinib in patients with MET amplified metastatic CRC.

II. To describe the toxicities of savolitinib in patients with MET amplified metastatic CRC.

III. To explore the effect of RAS mutation status on response to savolitinib. IV. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE:

Patients receive savolitinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 12 weeks thereafter for up to 2 years.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic and/or unresectable
* Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in BRAF codon 600, based on tumor tissue taken from primary or metastatic site prior to anti-EGFR antibody treatment
* At least one site of disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
* MET amplification detected by the Guardant360 circulating free deoxyribonucleic acid (cfDNA) screening assay (MET copy number \>= 2.2)
* Clinical or radiographic progression on treatments containing a fluoropyrimidine (e.g., 5- fluorouracil or capecitabine), oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody (bevacizumab, ziv-aflibercept) or anti-VEGFR monoclonal antibody (ramucirumab), and an anti-PD1 monoclonal antibody (nivolumab or pembrolizumab) for patients with microsatellite instability (MSI)-high/mismatch repair (MMR) deficient tumors, or the treatments were not tolerated or contraindicated
* Clinical or radiographic progression on prior anti-EGFR antibody therapy (either panitumumab or cetuximab)
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky \>= 80%)
* Absolute neutrophil count (ANC) \>= 1,500/mcL
* Hemoglobin (Hgb) \>= 9 g/dL (no transfusion in the past 2 weeks)
* Platelets \>= 100,000/mcL (no transfusion in the past 10 days)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x the institutional upper limit of normal (ULN) with total bilirubin (TBL) =\< 1 x ULN OR
* Total bilirubin (TBL) \> ULN =\<1.5 × ULN with ALT and AST =\< 1x ULN
* Glomerular filtration rate (GFR) \>= 60 mL/min/1.73 m\^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m\^2
* International normalization ratio (INR) \< 1.5 x ULN and activated partial thromboplastin time (aPTT) \< 1.5 x ULN unless patients are receiving therapeutic anticoagulation which affects these parameters
* Females of childbearing potential should be willing to use adequate contraceptive measures, should not be breast feeding, and must have a negative pregnancy test if of childbearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:

  * Post-menopausal is defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments; women under the age of 50 years would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution; or women with documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
* Male patients with female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug
* Ability to swallow and retain oral medications
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g. cytokines or antibodies) within 3 weeks of first dose of study treatment
* Not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =\< grade 1 from adverse events due to all prior anti-cancer therapies except alopecia, oxaliplatin-related neuropathy, and other non-clinically significant adverse events
* Any other investigational agents within 21 days before the first dose of study treatment
* Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered =\< 28 days or limited field radiation for palliation =\< 7 days prior to starting study drug or has not recovered from side effects of such therapy
* Known brain metastases. (Radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patient is asymptomatic, and no steroids have been administered for at least 30 days)
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to savolitinib
* Prior treatment with a small molecule inhibitor of c-MET or monoclonal antibody against c-MET or HGF
* Any of the following concurrent medication use:

  * Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (dhea), yohimbe, saw palmetto, and ginseng. Patients should stop using these herbal medications 7 days prior to first dose of study drug (three weeks for St. John's wort)
  * Patients receiving or requiring strong inducers or strong inhibitors of CYP3A4, strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks of the first dose of study treatment (3 weeks for St John's wort) will be excluded
  * Concomitant use of drugs that are known to be strong inhibitors of CYP3A4 or CYP1A2 is not permitted during the trial or must be stopped at least 2 weeks prior to receiving the first dose of savolitinib
* Any of the following cardiac disease currently or within the last 6 months:

  * Unstable angina pectoris
  * Congestive heart failure (New York Heart Association \[NYHA\]) \>= grade II
  * Acute myocardial infarction
  * Stroke or transient ischemic attack
* Known hypersensitivity to the active or inactive excipients of AZD6094
* Uncontrolled hypertension (blood pressure \[BP\] \>= 150/95 mmHg despite medical therapy)
* Active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea grade \>= 2, and malabsorption syndrome)
* Mean resting correct QT interval (Fridericia's correction formula \[QTcF\]) \> 470 msec for women and \> 450 msec for men on screening obtained from 3 electrocardiograms (ECGs)
* Any factors that may increase the risk of QTc prolongation such as chronic hypokalemia not correctable with supplements, congenital or familial long QT syndrome; or family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medications known to prolong QT interval and cause Torsades de Pointes (TdP)
* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiograms (ECGs), e.g. complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec
* Major surgical procedures =\< 28 days of beginning study drug or minor surgical procedures =\< 7 days. No waiting is required following port-a-cath placement
* Serious underlying medical condition at the time of treatment that would impair the ability of the patient to receive protocol treatment
* Active hepatitis B (positive hepatitis b virus \[HBV\] surface antigen \[HBsAg\] result) or hepatitis C (hepatitis C virus \[HCV\]) infection. Patients with positive HCV antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Patients with a past or resolved HBV infection are eligible if:

  * Negative for HBsAg and positive for hepatitis B core antibody \[anti-HBc\] OR
  * Positive for HBsAg, but for \> 6 months have had normal transaminases and HBV DNA levels between 0-2000 IU/ml (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study OR
  * HBV DNA levels \> 2000 IU/ml but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study
* Known serious active infection requiring antibiotic, antiviral or antifungal therapy. Human immunodeficiency virus (HIV)-positive patients are eligible only if meeting ALL criteria below:

  * No history of acquired immunodeficiency syndrome (AIDS)-defining conditions
  * Has been on the current highly active antiretroviral therapy (HAART) regimen for the past 3 months and will remain on the same regimen during the study
  * Current HAART regimen has a low potential for drug-drug interaction with the study drug
  * HIV viral load consistently below detectable limit for the past 3 months
  * CD4 count consistently \> 200 cells/mm\^3 for the past 3 months
* Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Patients with stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely (less than 5% probability) to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer
* Psychiatric illness/social situations that would limit compliance with study requirements. Patients with impaired decision-making capacity who have a close caregiver or legal guardian are also eligible with the consent of the caregiver/guardian
* Judgment by the investigator that the patients should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements