GNS561-221-1

Study Name
	GNS561-221-1
ClinicalTrials.gov Identifier (if applicable)
	NCT05874414
Clinical Trial Category (check all that apply)
	Beyond First Line Therapy Targeted Therapy
Study Center
Institution Name
	Pan American Center for Oncology Trials, LLC
Institution Address
	Hospital Oncológico Dr. Isaac González Martínez, 150 Av. Centro Médico San Juan, Puerto Rico 00935 United States Map It
Phone
	+1 787-407-3333
Website
	https://panoncologytrials.com
List additional Institutions (include address, phone number, and website)
	 USC Norris Comprehensive Cancer Center – 1441 Eastlake Ave, Los Angeles, CA 90033 – (323) 865-3000 – https://www.keckmedicine.org/locations/1441-eastlake-ave-los-angeles/  Roswell Park Cancer Institute – 665 Elm St, Buffalo, NY 14203 – (716) 845-2300 – https://www.roswellpark.org/  The University of Texas MD Anderson Cancer Center – 1515 Holcombe Blvd, Houston, TX 77030 – (877) 632-6789 – https://www.mdanderson.org/  University of Virginia Comprehensive Cancer Center – 200 Jeanette Lancaster Way, Charlottesville, VA 22903 – (434) 924-9637 – https://med.virginia.edu/hematology-oncology/about/contact-info/  University of Pennsylvania Abramson Cancer Center– 3400 Civic Center Boulevard, Philadelphia, PA 19104 – (215) 662 6065- Abramson Cancer Center | Penn Medicine – https://www.pennmedicine.org/cancer  University of Chicago Medical Center – 5841 S. Maryland Avenue; MC 2115, Chicago, IL 60637 – (773) 702 6241 – University of Chicago – Department of Medicine – Educating Future Doctor’s of the World (uchicago.edu) – https://medicine.uchicago.edu/  Froedtert Hospital and the Medical College of Wisconsin – 9200 W. Wisconsin, Milwaukee WI 53226 – (414) 805 0505 – Cancer Diagnosis, Treatment in Milwaukee | Froedtert & MCW – https://www.froedtert.com/cancer
Study Contacts
Principal Investigator
	Dr. Marcia Cruz-Correa
P.I. Phone
	+1 (787) 407-3333
P.I. Email
	info@panoncologytrials.com
List additional Principal Investigators (include phone number and email)
	Institution Name*: Pan American Center for Oncology Trials, LLC (630001) Institution Address: Hospital Oncológico Dr. Isaac González Martínez, 150 Av. Centro Médico City: San Juan State: Puerto Rico Zip Code: 00935 Country: USA Phone: +1 787-407-3333 PI: Marcia Cruz-Correa, marcia.cruzcorrea@panoncologytrials.com, Institution Name*: The University of Texas – MD Anderson Cancer Center – Nellie B. Connally Breast Center (840001) Institution Address: 1220 Holcombe; Mays Clinic Fl 5 City: Houston State: TX Zip Code: 77030 Country: USA Phone: 713-792-2073 PI: Milind Javle, mjavle@mdanderson.org Institution Name*: University of Pennsylvania (840003) Institution Address: 3451 Walnut St. City: Philadelphia State: PA Zip Code: 19104 Country: USA Phone: 215 662 6065 PI: Thomas Karasic, thomas.karasic@pennmedicine.upenn.edu Institution Name*: The University of Chicago Medical Center (840005) Institution Address: 5841 S. Maryland Avenue, MC 2115 City: Chicago State: IL Zip Code: 60637 Country: USA Phone: 773-702-6241 PI: Andy Liao, Andy.liao@medicine.bsd.uchicago.edu Institution Name*: Roswell Park Cancer Institute (840006) Institution Address: Elm and Carlton St City: Buffalo State: NY Zip Code: 14263 Country: USA Phone: 678 – 462 -2233 PI: Kannan Thanikachalam, Kannan.Thanikachalam@RoswellPark.org Institution Name*: University of Virginia Cancer Center – Emily Couric Clinical Cancer Center (840007) Institution Address: 6171 W Complex City: Charlottesville State: VA Zip Code: 22908 Country: USA Phone: 434-924-9333 PI: Matthew Reilley, 434-924-9333, MR7DB@hscmail.mcc.virginia.edu Institution Name*: USC Norris Comprehensive Cancer Center (840008) Institution Address: 1441 Eastlake Ave City: Los Angeles State: CA Zip Code: 90033 Country: USA Phone: 323-865-3000 PI: Anthony El-Khoueiry, elkhouei@med.usc.edu, 323-865-3000 Institution Name*: Froedtert Hospital and the Medical College of Wisconsin (840011) Institution Address: 9200 W. Wisconsin, Milwaukee WI 53226 City: Milwaukee State: WI Zip Code: 90033 Country: USA Phone: 414-805-0505 PI: Ben George, bgeorge@mcw.edu
Study Coordinator
	Guillermo Pico
Study Coordinator Phone
	(787) 407-3333
Study Coordinator Email
	guillermo.pico@panoncologytrials.com
List additional Study Coordinators (include phone number and email)
	Institution Name*: The University of Texas – MD Anderson Cancer Center – Nellie B. Connally Breast Center (840001) Institution Address: 1220 Holcombe; Mays Clinic Fl 5 City: Houston State: TX Zip Code: 77030 Country: USA SC: Jessica McKinley – JJMcKinley@mdanderson.org, 713-703-4354 Institution Name*: University of Pennsylvania (840003) Institution Address: 3451 Walnut St. City: Philadelphia State: PA Zip Code: 19104 Country: USA SC: Jennifer Walsh, jennifer.walsh4@pennmedicine.upenn.edu, 609-668-0689 Institution Name*: The University of Chicago Medical Center (840005) Institution Address: 5841 S. Maryland Avenue, MC 2115 City: Chicago State: IL Zip Code: 60637 Country: USA SC: Aurelie Desgardin, adesgard@bsd.uchicago.edu, 773-834-7188 Institution Name*: Roswell Park Cancer Institute (840006) Institution Address: Elm and Carlton St City: Buffalo State: NY Zip Code: 14263 Country: USA SC: Alexandra House, 716-845-1300, ext 3641, Alexandra.House@RoswellPark.org Institution Name*: University of Virginia Cancer Center – Emily Couric Clinical Cancer Center (840007) Institution Address: 6171 W Complex City: Charlottesville State: VA Zip Code: 22908 Country: USA SC: Amanda Neider, 434-243-8237, aln4k@uvahealth.org Institution Name*: Froedtert Hospital and the Medical College of Wisconsin Institution Address: 9200 W. Wisconsin, Milwaukee WI 53226 City: Milwaukee State: WI Zip Code: 90033 Country: USA Phone: 414-805-3158 SC: Colleen Cotter, cmcotter@mcw.edu Institution Name*: USC Norris Comprehensive Cancer Center (840008) Institution Address: 1441 Eastlake Ave City: Los Angeles State: CA Zip Code: 90033 Country: USA SC: Carryl Du Bois, Carryl.DuBois@med.usc.edu, 323 865 3084
OVERVIEW – in layman’s terms (150 words max)
	GNS561 is an inhibitor of autophagy, a protective mechanism that allows tumor cells to be resistant to cancer treatments. Trametinib (“T”) is a drug that blocks the action of proteins that help cancer cells to grow. KRAS mutation in cancer cells may lead to the production of proteins helping cancer cells to grow. “T” might block those proteins, but cancer cells might find another way to grow (autophagy). Adding an inhibitor of autophagy, like GNS561, to “T”, may help to treat patients with CCA with a KRAS mutation. This study [(https://www.clinicaltrials.gov), NCT05874414)] aims to determine the recommended dose of the combination for Phase 2 (RP2DC) and to assess preliminary efficacy/safety of GNS561+”T” in patients with advanced KRAS-mutated CCA.
Enrollment
	Up to 74
Study Start Date
	08/21/2023
Estimated Completion Date
	10/31/2026
Purpose of the Study – in Layman’s Terms (use the “+” to add more list items)
	Open label, multi-center, Phase 1b/2a study (NCT05874414) Evaluation of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of GNS561+T in adult patients with advanced histologically confirmed KRAS-mutated CCA not amenable to local treatment with surgery or radiotherapy, or with metastatic disease not responding to Standard of Care. Patients are treated in 21-day cycles. Phase 1b (P1b) is conducted in to determine the maximum tolerated doses of GNS561+T. The RP2DC in Phase 2a (P2a) will be based on safety, PK, and PD data from P1b.
Inclusion Criteria – Patients Must:
	1. Histologically confirmed CCA with a documented KRAS mutation. 2. Patients greater than or equal to 18 years of age. 3. Patients must have disease progression that is not amenable to potentially curative treatment. 4. Patients must have received at least one line of chemotherapy. 5. Patients must have at least one measurable disease by RECIST v1.1. 6. Performance status (ECOG) 0-1. 7. Adequate organ baseline function defined as follows: absolute neutrophil count ≥1500 cells/μL, platelet count ≥100,000 cells/μL, hemoglobin ≥9 g/dL, aspartate aminotransferase or alanine aminotransferase less than or equal to 5 × upper limit of normal, estimated glomerular filtration rate ≥60 mL/min, corrected QT interval by Fridericia’s (QTcF) interval ≤470 msec. 8. Women of childbearing potential must present with a negative serum pregnancy test and agree to use adequate contraception during the study and until 6 months after the end of treatment. Male patients with women partners of childbearing potential must agree with the contraception procedures of the study protocol. 9. Patients must be able to understand and be willing to comply with the requirements of the study protocol. 10. Patients participate voluntarily and sign informed consent form(s).
Exclusion Criteria – Patients Must NOT:
	1. Previous treatment with a MEK inhibitor or autophagy inhibitor. 2. Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions: a) Cardiovascular disorders: congestive heart failure New York Heart Association ≥ class 2 or left ventricular ejection fraction (LVEF) <50%, arrythmias or cardiac conduction abnormalities, history of coronary disease (including myocardial infarction, unstable angina), history of angioplasty or stenting within 6 months prior to enrollment. b) Patients who have retinal condition (retinal tear, exudate, hemorrhage) or history of retinal vein occlusion or central serous retinopathy or retinal pigment epithelial detachment. c) History of interstitial lung disease or pneumonitis. d) Patients who have clinically significant pleural effusion or ascites. e) Patients who have neurological condition (e.g., tremor, ataxia, hypotension, confusion), history of seizures or active central nervous system metastases. f) Impairment of gastrointestinal function or gastrointestinal disease (e.g., diarrhea, active ulcer disease, history of gastrointestinal perforation/hemorrhage, malabsorption or other conditions that under the judgment of the principal investigator (PI) may impair absorption of study drugs). g) Patients who are taking antineoplastic drugs for concomitant cancer or history of another malignancy with the exception of patients who have been disease-free for at least 3 years. h) Any other condition that would, in the Investigator s judgment, contraindicate the patients’ participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection, unable to swallow medication, social/psychological issues, etc). 3. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, or inherited liver disease as well as active viral disease including HBV and HCV. 4. Patients with known allergic reaction to quinoline derivatives (e.g., quinine, chloroquine, mefloquine) and/or hypersensitivity to study drugs. 5. Female patients who are pregnant or lactating at the time of enrollment.
REQUIRED TESTS PRIOR TO BEGINNING STUDY TREATMENT – in layman’s terms
	Before the first study procedure can be done, you will be asked to sign a consent form in duplicate, and you will keep one of the copies. As soon as you have signed the informed consent form, a patient number will be assigned to you for the entire study in order to keep your identity confidential. During this first screening visit, your Study Doctor, or a member of the study team, will perform the following assessments: o Your Study Doctor will inform you about this clinical study. o You will be asked about your medical history (including your smoking status) and your previous anticancer treatment. o You will be asked if you agree to give access to your medical record to check if a KRAS mutation test in a tumor sample has been already done and if not to test for the presence of the KRAS mutation in a previous CCA tumor biopsy. In case there is no previous tumor biopsy tissue available, you will undergo, as per local practice, a new tumor biopsy procedure to collect a fresh tumor tissue. This tissue sample will be used to assess the presence of the KRAS mutation in your tumor tissue. o You will be asked to give a blood sample that will be used to check for the presence or absence of a KRAS mutation in your circulating tumor cells (liquid biopsy). If these assessments and procedures show that you can take part in the study, and you choose to take part, you will pursue the screening period and attend the Screening Visit 2 (SV2). If these assessments and procedures show that you cannot continue to the next phase of the study, you will not be enrolled in the study.  Screening Visit 2 (SV2) During this visit, your Study Doctor, or a member of the study team, will perform the following assessments: o You will be asked about your prior and ongoing treatments. o A physical examination including measurement of your height, body weight, assessment of skin, head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; lymph nodes; as well as a neurological examination will be performed. It will include vital signs: blood pressure, body temperature, pulse rate and respiratory rate. It will also include a performance status (e.g., how well you are able to perform your activities of daily living). o ECGs will be performed after you have been laying down for at least 5 minutes. They will be analyzed by your Study Doctor. o Blood samples will be collected for laboratory assessments to check your health and to see if you have been exposed to HIV, hepatitis B or hepatitis C infection. If your test results reveal an HIV infection, you will be told and given information on counseling services. Also, your Study Doctor or staff will tell you if your test results are positive for hepatitis B or C. The results of your HIV, hepatitis B, or C testing will be kept confidential and disclosed only within limits required by law. In the event of an active HIV infection, active hepatitis B, or active hepatitis C, you will not continue the study and your Study Doctor will advise you for the next steps to follow. O Blood samplings for tumor markers will be taken. Patients with your cancer might have raised level(s) of specific tumor marker(s) in their blood. If it is the case, level(s) of your tumor marker(s) will be measured at specific visits (described below). In order to be able to test other specific parameters which could be of interest regarding the exploratory objectives of the study, an additional optional sub-study will be proposed to collect other blood samples and perform other analyses. This biological sample collection and related analyses will only be performed if you have voluntarily given your explicit consent beforehand by signing a dedicated Consent Form. As collection of vital signs is scheduled at the same time as blood samples and ECGs, the order of assessments will be ECGs, vital signs, and blood samples last. o If you are a female of childbearing potential, a blood pregnancy test will be performed. You will not be able to take part in the study if you are pregnant or intend to become pregnant or lactating during the study. For this reason, you will have to use a highly effective contraception methods during the study: – Highly effective non-hormonal methods of contraception (bilateral tubal occlusion, vasectomized partner, or intra-uterine device) – Highly effective hormonal method of contraception (oral, intravaginal or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation; oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation or intrauterine hormone-releasing system). – Highly effective contraception must be used for the full duration of the study and for six months after the end of treatment. o A urine sample will be collected. SV2 might be divided into at least 4 visits (a Study Doctor visit, a visit with the cardiologist, a visit with the ophthalmologist and a visit at the imaging facility). For each of these assessments (imaging tests, eye assessment and heart assessment), a dedicated visit will occur with each dedicated health specialists: o Imaging tests – Computed tomography (CT) and/or MRI (Magnetic Resonance Imaging) scans (pelvis, abdomen, chest, and head, and possibly other part(s) of your body according to your Study Doctor judgment) will be performed to identify the areas of cancer in your liver and body. If you have had either of these tests within the last 4 weeks, you may not have to have them again. o Eye examinations to evaluate different eye parameters will be assessed by an eye doctor (ophthalmologist). o Heart assessment either with an echocardiogram or MUGA scan will be performed to check your heart function. Upon receipt of your test results, the Study Doctor will check the criteria for entry into the study. If needed, some blood tests, other procedures, or dedicated visits (for example eye examinations or heart assessment) may need to be repeated to confirm your eligibility [see below paragraph “Retesting screening visit(s)”]. Upon availability of all the results, you will be informed of your eligibility before the first visit of the treatment period. If the result of the tests shows that you cannot continue to the next phase of the study, you will not be included in the study. If you continue in the study, your Study Doctor will schedule the next visit with you. ✓ Retesting screening visit(s): Upon receipt of results from assessments done during the screening phase and in case a retesting or additional testing is needed to confirm your eligibility, additional visit(s) would be scheduled.
POTENTIAL SIDE-EFFECTS – in layman’s terms
	There is a risk that you could have side effects from the study drugs.  GNS561 You may have unwanted effects and symptoms as a result of study treatment with GNS561. The most frequent known and potentially serious unwanted effects and symptoms may include: • gastrointestinal problems. Tell your Study Doctor right away if you have any of the following symptoms: o nausea o vomiting o diarrhea • Metabolism and nutrition disorders : decreased appetite, anorexia • General disorders: fatigue, asthenia. In another study being conducted by another Sponsor in patients with another type of liver cancer, one patient experienced severe diarrhea related to GNS561 intake that resulted in a fatal outcome. • liver enzymes increase in your blood test, which could indicate damage to the liver. • zinc decrease in your blood test, which could require zinc supplementation. GNS561 may also cause less frequent but potentially serious side effects: • new or worsening low blood pressure (hypotension). Call your Study Doctor right away if you develop low blood pressure, your blood pressure worsens, or you have lightheadedness, blurry vision, or dizziness. • new or worsening high blood pressure (hypertension). Call your Study Doctor right away if you develop high blood pressure, your blood pressure worsens, or you have lightheadedness, blurry vision, dizziness or headache. • Changes in the electrical activity of your heart. Call your Study Doctor and get medical help right away if you have any of the following symptoms: pounding heartbeats, lightheadedness, or blurry vision. Based on the mechanism of action of GNS561 and the fact that this study drug belongs to a group of drugs called “quinoline derivative”, side effects known for this type of drugs, but not reported for GNS561 so far will be also monitored: • heart problems such as cardiomyopathy, a disease of the heart muscle that makes it harder for the heart to pump blood to the rest of your body. Your Study Doctor will check your heart function before and during treatment with GNS561. Call your Study Doctor and get medical help right away if you have any of the following signs and symptoms of a heart problem: o feeling like your heart is pounding or racing o shortness of breath o swelling of your ankles and feet o feeling lightheaded o fatigue (feeling tired). This study includes regular visits with heart assessments including ECGs and echocardiograms to monitor for any potential heart problems that may be related to GNS561.  Trametinib You may have unwanted effects and symptoms as a result of study treatment with trametinib. The most frequent known unwanted effects and symptoms may include: • rash • diarrhea • swelling of the face, arms, or legs. Trametinib may also cause rare but potentially serious side effects: • bleeding problems. Trametinib can cause serious bleeding problems, especially in your brain or stomach, that can lead to death. Call your Study Doctor and get medical help right away if you have any signs of bleeding, including: o headaches, dizziness, or feeling weak o cough up blood or blood clots o vomit blood or your vomit looks like “coffee grounds” o red or black stools that look like tar. • inflammation of the intestines, or tears (perforation) of the stomach or intestines. Trametinib can cause inflammation of your intestines, or tears in the stomach or intestines that can lead to death. Tell your Study Doctor right away if you have any of the following symptoms: o bleeding. See “bleeding problems” above. o diarrhea (loose stools) or more bowel movements than usual o stomach-area (abdomen) pain or tenderness o fever o nausea. • blood clots. Trametinib can cause blood clots in your arms or legs, which can travel to your lungs and can lead to death. Get medical help right away if you have the following symptoms: o chest pain o sudden shortness of breath or trouble breathing o pain in your legs with or without swelling o swelling in your arms or legs o a cool pale arm or leg. • heart problems, including heart failure. Your Study Doctor should check your heart function before and during treatment with trametinib. Call your Study Doctor and get medical help right away if you have any of the following signs and symptoms of a heart problem: o feeling like your heart is pounding or racing o shortness of breath o swelling of your ankles and feet o feeling lightheaded. • eye problems. Trametinib can cause severe eye problems that might lead to blindness. Call your Study Doctor right away if you get these symptoms of eye problems: o blurred vision, loss of vision, or other vision changes o see color dots o halo (seeing blurred outline around objects) o eye pain, swelling, or redness. • lung or breathing problems. Trametinib can cause lung or breathing problems. Tell your Study Doctor if you have any new or worsening symptoms of lung or breathing problems, including: o shortness of breath o cough. • fever. In some cases, people with fever may develop chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems. Call your Study Doctor right away if you get a fever during treatment with trametinib. • serious skin reactions. Skin rash is a common side effect of trametinib. Trametinib can also cause other skin reactions. In some cases, these rashes and other skin reactions can be severe or serious and may need to be treated in a hospital or lead to death. Please tell your Study Doctor if you get a skin rash or acne that bothers you or worsens. Tell your Study Doctor right away if you develop any of the following signs or symptoms of a severe skin reaction, including: o blisters or peeling of your skin o blisters on your lips, or around your mouth or eyes o mouth sores o high fever or flu-like symptoms o enlarged lymph nodes. • cause new or worsening high blood pressure (hypertension). Your Study Doctor should check your blood pressure during treatment with trametinib. Call your Study Doctor right away if you develop high blood pressure, your blood pressure worsens, or you have severe headache, lightheadedness, blurry vision, or dizziness. • fertility problems in female participants. This could affect your ability to become pregnant. Talk to your Study Doctor if this is a concern for you. • potential fetal risk Before you take trametinib, please inform your Study Doctor about all your medical conditions, including if you: • have had bleeding problems or blood clots • have stomach problems • have inflammation of the colon • have heart problems • have eye problems • have lung or breathing problems • have high blood pressure (hypertension) • have liver or kidney problems • have diabetes • are pregnant or plan to become pregnant. Trametinib can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if trametinib passes into your breast milk. Talk to your Study Doctor about the best way to feed your baby during this time. Your Study Doctor will take all appropriate measures in case of any adverse event to ensure your safety until the return to normal or until stability of your condition. This may imply that safety follow-up may continue after you have left the study and that additional investigations may be requested by your Study Doctor or by the Sponsor, notably for potential related adverse events. Certain markers in your blood and urine that may suggest metabolic, liver, muscle, heart or kidney problems may also be affected by study drugs. All these parameters will be closely monitored during the study. As GNS561 is an experimental drug in development, it is possible that there may be unknown side effects. For trametinib, these side effects mentioned above are not all the possible side effects. If you suffer from any symptoms during the study (whether you believe it is related to the study drug or not, and whether or not it is listed above), you have to report them to your Study Doctor, even if it is not during the scheduled visit.
Financial Assistance is available to participants for travel, lodging, etc.
	Yes