Study Assessing Activity of Molecularly Matched Targeted Therapies in Select Tumor Types Based on Genomic Alterations

Phase II Study to Evaluate the Activity of Commercially Available Molecularly Matched Targeted Therapies in Selected Tumor Types Based on Genomic Alterations

With the increased availability of next-generation sequencing, oncologists are starting to incorporate genomic profiling into routine care of cancer patients. If a genomic alteration is identified during profiling, it could help guide the choice of therapy and improve treatment outcomes. This study will examine the anti-tumor activity of selected commercially available molecularly matched targeted therapies in patients who have failed first-line treatment for one of the following tumor types: non-small cell lung cancers; urothelial cancer; non-colon gastrointestinal cancers, and upper aerodigestive tract cancer.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Carcinoma; Urothelial Carcinoma; Gastrointestinal Carcinoma, Non-colon; Upper Aerodigestive Tract Carcinoma
• Intervention / Treatment: Drug: Afatinib; Drug: Regorafenib; Drug: Cabozantinib

Detailed Description

This four-arm pilot phase II study will evaluate the preliminary antitumor activity of selected commercially available molecularly matched targeted therapies in patients who have failed first line treatment for one of the following tumor types:

1. non-small cell lung cancer,
2. urothelial carcinoma,
3. non-colon gastrointestinal cancers, and
4. upper aerodigestive tract cancers (lip, tongue, salivary glands, gum, mouth, oral cavity, tonsils, oropharynx, nasopharynx, nasal cavity, sinus, and larynx tumors).

Approximately 160 patients (40 per tumour type) are planned for enrollment. Consideration for enrollment will be based on results from profiling with next-generation sequencing technology that was performed outside of the protocol. Eligible patients will receive one of the FDA-approved targeted agents at the recommended dose. The treating physician will decide which targeted agent to prescribe based on the genomic alterations per tumor type and the targets listed in the package insert for each agent.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute at HealthONE
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists - South
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - North
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists - East
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center - HCA Midwest
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennesse Oncology
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with a histologically or cytologically confirmed diagnosis of one of the following tumor types whose disease has progressed following one line of standard therapy and/or for which no standard treatment is available that has been shown to prolong survival:

   1. Non-small cell lung cancer
   2. Urothelial carcinoma
   3. Non-colon gastrointestinal cancers (including hepatobiliary, pancreatic, and gastroesophageal tumors)
   4. Upper aerodigestive tract cancers (including lip, tongue, salivary gland, gum, oral cavity, mouth, tonsils, oropharynx, nasopharynx, nasal cavity, sinus, and larynx tumors)
2. Patients must have a predefined genomic alteration that can be targeted with any of the FDA-approved targeted agents used in this study.
3. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
5. Age greater than or equal to 18 years.

6. Adequate hematologic function defined as:

   • Absolute neutrophil count (ANC) ≥1500/μL
   • Platelets ≥75,000/μL

7. Adequate liver function defined as:

   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x the upper limit of normal (ULN) or ≤ 5.0 X ULN if liver metastases present
   • Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin)
8. Adequate renal function defined as serum creatinine ≤1.5 x the upper limit of normal OR measured or calculated creatinine clearance ≥50 mL/min for patients with creatinine levels greater than or equal to 1.5 x the upper limit of normal.
9. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to receive either regorafenib or afatinib provided that their medication dose and INR/PTT are stable. Close monitoring is mandatory if the patient is receiving anticoagulants. If values are above the therapeutic range the anticoagulant doses should be modified and assessments should be repeated until stable.
10. Male patients with female partners of childbearing potential and women patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 90 days following last dose of study drug(s). Male patients must also refrain from donating sperm during their participation in the study and for 90 days after the last dose of study drug.
11. Willingness and ability to comply with study and follow-up procedures.
12. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

1. Two or more prior chemotherapy regimens in the metastatic setting.
2. Most recent chemotherapy ≤ 3 weeks and > Grade 1 chemotherapy-related side effects, with the exception of neuropathy (> grade 2 excluded) and alopecia.
3. Use of a study drug or targeted therapy ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of study treatment is required.
4. 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.
5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement.
6. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 2 weeks prior to study entry and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy. Enzyme-inducing anticonvulsants are contraindicated.
7. Pregnant or lactating
8. Acute or chronic liver, renal, or pancreas disease.
9. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy.

10. Any of the following cardiac diseases currently or within the last 6 months:

    • Unstable angina pectoris
    • Congestive heart failure (New York Heart Association (NYHA) ≥ Grade 2
    • Acute myocardial infarction
    • Conduction abnormality not controlled with pacemaker or medication
    • Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
    • Valvular disease with significant compromise in cardiac function
11. Inadequately controlled hypertension.
12. Thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of treatment.
13. Evidence or history of bleeding diathesis or coagulopathy; any haemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of treatment.

14. For patients receiving cabozantinib only: Do not administer cabozantinib to patients that have high risk or at high risk for severe haemorrhage. Examples include:

    1. The patient has radiographic evidence of cavitating pulmonary lesion(s).
    2. The patient has tumor invading or encasing any major blood vessels.
    3. The patient has had hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment.
    4. The patient has experienced clinically significant GI bleeding within 6 months of the first dose of study treatment.
    5. The patient has experienced any other signs indicative of pulmonary hemorrhage within 3 months of the first dose of study treatment.

15. For patients receiving cabozantinib only: Do not administer cabozantinib to patients that have high risk or at high risk of perforation or fistula:

    1. The patient has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.
    2. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose.
    3. The patient has pre-existing fistula of head and neck area. Note: Treatment areas should be healed with no sequelae from prior radiation therapy that would predispose to fistula formation.
    4. The patient has pre-existing osteonecrosis of the jaw.
16. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors. [Patients receiving cabozantinib only]
17. Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen.Presence of a non-healing wound, non-healing ulcer, or bone fracture.
18. Patients with phaeochromocytoma.
19. Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
20. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.
21. Presence of other active cancers unless indolent and not requiring therapy. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma are eligible, as are patients with history of non-melanoma skin cancer.
22. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Patients with non-small cell lung cancer who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations.	Drug: Afatinib; 40 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Gilotrif; Drug: Regorafenib; 160 mg orally once daily for the first 21 days of each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Stivarga; Drug: Cabozantinib; 60 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Cabometyx
Experimental: Arm 2; Patients with urothelial carcinoma who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations.	Drug: Afatinib; 40 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Gilotrif; Drug: Regorafenib; 160 mg orally once daily for the first 21 days of each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Stivarga; Drug: Cabozantinib; 60 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Cabometyx
Experimental: Arm 3; Patients with non-colon gastrointestinal cancers who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations.	Drug: Afatinib; 40 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Gilotrif; Drug: Regorafenib; 160 mg orally once daily for the first 21 days of each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Stivarga; Drug: Cabozantinib; 60 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Cabometyx
Experimental: Arm 4; Patients with upper aerodigestive tract cancers who have failed first line treatment may receive either regorafenib (Stivarga), afatinib (Gilotrif), or cabozantinib (Cabometyx) at the recommended dose level, depending on their specific genomic alterations.	Drug: Afatinib; 40 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Gilotrif; Drug: Regorafenib; 160 mg orally once daily for the first 21 days of each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Stivarga; Drug: Cabozantinib; 60 mg orally once daily for each 28-day cycle. Treatment will continue until disease progression or intolerable toxicity or other reason for discontinuation up to 45 months.; Other Names: Cabometyx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) in Each Arm Receiving Targeted Therapy Based on Relevant Genomic Alterations	ORR is defined as the percentage of patients with confirmed complete response (CR) or confirmed partial response (PR), i.e., two CRs and/or PRs at least 4 weeks apart, according to the RECIST v1.1 criteria. CR=disappearance of all target and non-target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.	every 8 weeks until tumor progression or treatment discontinuation, up to 45 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Rate in Each Arm Receiving Targeted Therapy Based on Relevant Genomic Alterations	Clinical Benefit Rate (CBR) is defined as the percentage of patients with confirmed complete response (CR) or confirmed partial response (PR) or stable disease (SD) ≥ 6 months according to RECIST v1.1. Confirmed response is defined as two CRs and/or PRs at least 4 weeks apart, according to the RECIST v1.1 criteria. CR=disappearance of all target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease= Neither sufficient shrinkage to qualify for PR nor sufficient increase of 20% in the sum of diameters or presence of a new lesion to qualify for progressive disease (PD), taking as reference the smallest (nadir) sum of diameters since the treatment started.	Every 8 weeks until tumor progression or treatment discontinuation, up to 45 months
Time to Treatment Failure (TTF) in Each Arm Receiving Targeted Therapy Based on Relevant Genomic Alterations	Time to treatment failure is measured from the first day of treatment until the patient is removed from study for toxicity, disease progression per RECIST v1.1, patient choice, or death. Progressive disease (PD) per RECIST v1.1 is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum since the treatment started, or the appearance of one or more new lesions. Requires not only 20% increase, but absolute increase of a minimum of 5 mm over the sum.	Every 8 weeks until tumor progression or treatment discontinuation, up to 45 months
Progression-Free Survival in Each Arm Receiving Targeted Therapy Based on Relevant Genomic Alterations	Progression Free Survival (PFS) is defined as the time from the first day of study drug administration (Day 1) to disease progression as defined by the RECIST v1.1, or death on study. Patients who are alive and free from disease progression will be censored at the date of last tumor assessment. Progressive disease (PD) per RECIST v1.1 is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum since the treatment started, or the appearance of one or more new lesions. Requires not only 20% increase, but absolute increase of a minimum of 5 mm over the sum.	Every 8 weeks until tumor progression or treatment discontinuation, up to 45 months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Bayer; Boehringer Ingelheim; Exelixis; Foundation Medicine
• Investigators: Study Chair: Howard A. Burris, III, MD, SCRI Development Innovations, LLC

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2016
• Primary Completion (Actual): August 17, 2022
• Study Completion (Actual): August 17, 2022

Study Registration Dates

• First Submitted: June 6, 2016
• First Submitted That Met QC Criteria: June 8, 2016
• First Posted (Estimated): June 9, 2016

Study Record Updates

• Last Update Posted (Actual): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: targeted therapy; cabozantinib; regorafenib; afatinib
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: SCRI PRO 10

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No