GSK3359609 Plus Tremelimumab for the Treatment of Advanced Solid Tumors

NCT03693612 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 207871
• Study Type: interventional
• Target: 26
• Locations: 3 countries
• Sites: 8

Brief Summary

The purpose of this study is to evaluate if the combination of GSK3359609 and tremelimumab is safe and tolerable (Part 1) and provides significant survival benefit to subjects with relapsed/refractory (R/R) Head and Neck Squamous Cell Carcinomas (HNSCC) to warrant further clinical investigation (Part 2). Part 1 (dose escalation) will enroll subjects with advanced, selected solid tumors. Subjects will receive escalating doses of GSK3359609 and tremelimumab in combination in Part 1. Part 2 is randomized expansion and will enroll subjects with R/R HNSCC who have disease progression after receiving at least 1 platinum-based chemotherapy and at least 1 anti-programmed death receptor protein-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy, whether in combination or separately. In Part 2, subjects will be randomized in a ratio of 2:1 to receive either GSK3359609 in combination with tremelimumab at the recommended Phase 2 dose or investigators choice of a single-agent standard of care (SOC) therapy including paclitaxel, docetaxel or cetuximab. The total duration of subjects in the study will be approximately 4 years.

Conditions

Neoplasms

Keywords

advanced solid tumor; Head and Neck Squamous Cell Carcinoma; standard of care; GSK3359609; urothelial carcinoma of the upper and lower urinary tract; non-small cell lung cancer; cutaneous melanoma; Tremelimumab; clear cell renal carcinoma; castrate resistant prostate adenocarcinoma

Outcome Measures

Primary Outcomes (28)

• Number of Participants With Dose Limiting Toxicities (DLTs)-Part 1

  A DLT is considered by the investigator to be clinically relevant, attributed event within first 28 days of intervention meeting the following criteria of toxicity, Hematologic: Febrile neutropenia, Grade 4 neutropenia of greater than (\>) 7 days in duration or requiring Granulocyte- Colony stimulating factor (G-CSF), Grade 4 anemia and Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; Non-hematologic: Grade 4 toxicity, Grade 3 pneumonitis, any greater than or equal to (≥) Grade 2 pneumonitis that does not resolve to less than or equal to (≤ ) Grade 1 within 3 days of the initiation of maximal supportive care, Grade 3 toxicity that does not resolve to Grade 1 or baseline within 3 days despite optimal supportive care and any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 ocular toxicity.

  Up to 28 days

• Number of Participants With DLTs According to Severity-Part 1

  The severity of all toxicities were graded using the National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. Grade 1: Mild reaction; infusion interruption not indicated; intervention not indicated; Grade 2: Requires therapy or infusion interruption but responds promptly to symptomatic treatment or prophylactic medications indicated for ≤24 hours; Grade 3: Prolonged (i.e., not rapidly responsive to symptomatic medication and/or brief interruption of infusion) or recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae; Grade 4: Life-threatening; pressor or ventilatory support indicated; Grade 5: Death related to AE.

  Up to 28 days

• Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)-Part 1

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect and important medical events may jeopardize the subject or may require medical or surgical intervention/SOC to prevent one of the other outcomes mentioned before. AESIs are defined as events of potential immunologic etiology, including immune related AEs.

  Up to 4 years

• Number of Participant With AE/SAE/DLTs Leading to Dose Modifications/Delays/Withdrawals-Part 1

  The number of participants with AE/SAE/DLTs leading to dose modifications/delays/withdrawals were summarized.

  Up to 4 years

• Number of Participants With AEs, SAEs, AESIs According to Severity - Part 1

  The severity of all toxicities were graded using the National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. Grade 1: Mild reaction; infusion interruption not indicated; intervention not indicated; Grade 2: Requires therapy or infusion interruption but responds promptly to symptomatic treatment or prophylactic medications indicated for ≤24 hours; Grade 3: Prolonged (i.e., not rapidly responsive to symptomatic medication and/or brief interruption of infusion) or recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae; Grade 4: Life-threatening; pressor or ventilatory support indicated; Grade 5: Death related to AE.

  Up to 4 years

• Number of Participants With Severe- AEs/SAEs/DLTs Leading to Dose Modifications/Delays/Withdrawals-Part 1

  The number of participants with severe- AE/SAE/DLTs leading to dose modifications/delays/withdrawals were summarized.

  Up to 4 years

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1

  SBP and DBP were measured after 5 minutes of rest for the participant.

  Baseline (Day 1) and Week 4

• Change From Baseline in Temperature-Part 1

  Temperature was measured after 5 minutes of rest for the participant.

  Baseline (Day 1) and Week 4

• Change From Baseline in Pulse Rate-Part 1

  Pulse rate was measured after 5 minutes of rest for the participant.

  Baseline (Day 1) and Week 4

• Change From Baseline in Respiratory Rate-Part 1

  Respiratory rate was measured after 5 minutes of rest for the participant.

  Baseline (Day 1) and Week 4

• Change From Baseline in Oxygen Saturation-Part 1

  Oxygen saturation was measured using pulse oximeter after 5 minutes of rest for the participant.

  Baseline (Day 1) and Week 4

• Number of Participants With Electrocardiogram (ECG) Findings

  Single 12-lead ECG was obtained using an automated ECG machine. ECG findings were categorized as: normal, abnormal - clinically significant (CS), or abnormal - not clinically significant (NCS), as determined by the investigator.

  Baseline (Pre dose, Day 1) and up to 4 Years

• Change From Baseline in Neutrophil, Lymphocyte, Monocyte, Eosinophil, Basophil and Platelet Count-Part 1

  Blood samples were collected to assess change from Baseline in neutrophil, lymphocyte, monocyte, eosinophil, basophil and platelet counts.

  Baseline (Day 1) and Week 4

• Change From Baseline in Hemoglobin Level-Part 1

  Blood samples were collected to assess change from baseline in hemoglobin level.

  Baseline (Day 1) and Week 4

• Change From Baseline in Hematocrit Level-Part 1

  Blood samples were collected to assess change from baseline in hematocrit level.

  Baseline (Day 1) and Week 4

• Change From Baseline in Erythrocytes Count-Part 1

  Blood samples were collected to assess change from baseline in Erythrocytes count.

  Baseline (Day 1) and Week 4

• Change From Baseline in Albumin and Total Protein Levels-Part 1

  Blood samples were collected to assess change from Baseline in albumin and total protein levels.

  Baseline (Day 1) and Week 4

• Change From Baseline in Creatinine and Bilirubin Levels-Part 1

  Blood samples were collected to assess change from baseline in creatinine and bilirubin levels.

  Baseline (Day 1) and Week 4

• Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Lactate Dehydrogenase (LDH) Levels-Part 1

  Blood samples were collected to assess change from baseline in ALT, AST ALP, LDH levels.

  Baseline (Day 1) and Week 4

• Change From Baseline in Amylase and Lipase Levels-Part 1

  Blood samples were collected to assess change from baseline in amylase and lipase levels.

  Baseline (Day 1) and week 4

• Change From Baseline in Urea, Glucose, Potassium, Sodium and Calcium Levels-Part 1

  Blood samples were collected to assess change in levels of urea, glucose, potassium, sodium and calcium from baseline.

  Baseline (Day 1) and Week 4

• Change From Baseline in Specific Gravity of Urine-Part 1

  Urine samples were collected to assess change from baseline in specific gravity of urine.

  Baseline (Day 1) and Week 4

• Change From Baseline in Potential of Hydrogen (pH) of Urine-Part 1

  Urine samples were collected to assess change from baseline in pH of urine.

  Baseline (Day 1) and Week 4

• Number of Participants With Abnormal Urinalysis Parameters-Part 1

  The dipstick test gives positive or negative results for protein, ketones, occult blood and glucose in urine. Positive test results were considered as abnormal. Number of participants with positive test results have been summarized.

  Week 4

• Change From Baseline in Thyroid Stimulating Hormone (TSH) or Thyrotropin-Part 1

  Blood samples were collected to assess change from Baseline in TSH.

  Baseline (Day 1) and Week 4

• Change From Baseline in Free Triiodothyronine (T3)-Part 1

  Blood samples were collected to assess change from Baseline in free T3.

  Baseline (Day 1) and Week 4

• Change From Baseline in Free Thyroxine (T4)-Part 1

  Blood samples were collected to assess change from baseline in free T4.

  Baseline (Day 1) and Week 4

• Overall Survival-Part 2

  For participants in Part 2, overall survival is defined as time from the date of randomization to the date of death due to any cause.

  Up to 4 years

Secondary Outcomes (47)

• Overall Response Rate-Part 1

  Up to 4 years

• Overall Response Rate-Part 2

  Up to 4 years

• Disease Control Rate-Part 1

  Up to 4 years

• Disease Control Rate-Part 2

  Up to 4 years

• Progression Free Survival-Part 2

  Up to 4 years

Study Arms (3)

Part 1: feladilimab +tremelimumab

EXPERIMENTAL

In Part 1, subjects with advanced selected solid tumors will be enrolled. Subjects will be administered escalating doses of feladilimab and tremelimumab in combination. feladilimab will be administered every 3 weeks and tremelimumab will be administered every 3 weeks for 6 doses and every 12 weeks thereafter.

Drug: feladilimab; Drug: Tremelimumab

Part 2: feladilimab +tremelimumab

EXPERIMENTAL

In Part 2, subjects with R/R HNSCC who have disease progression after receiving at least one platinum-based chemotherapy and at least one anti-PD-1/PD-L1 will be enrolled. Subjects will be administered feladilimab in combination with tremelimumab at recommended Phase 2 dose as determined from Part 1.

Drug: feladilimab; Drug: Tremelimumab

Part 2: SOC

ACTIVE COMPARATOR

In Part 2, subjects with R/R HNSCC who have disease progression after receiving at least one platinum-based chemotherapy and at least one anti-PD-1/PD-L1 will be enrolled. Subjects will be administered a single agent SOC therapy of either paclitaxel, docetaxel or cetuximab as per the investigators choice.

Drug: Docetaxel; Drug: Paclitaxel; Drug: Cetuximab

Interventions

feladilimab DRUG

feladilimab is humanized anti-ICOS agonist immunoglobulin G (IgG) 4 monoclonal antibody (mAb), which will be administered as an intravenous (IV) infusion once every 3 weeks.

Part 1: feladilimab +tremelimumab; Part 2: feladilimab +tremelimumab

Tremelimumab DRUG

Tremelimumab is humanized anti-CTLA-4 IgG2 mAb, which will be administered as an IV infusion once every 3 weeks for 6 doses, thereafter once every 12 weeks .

Part 1: feladilimab +tremelimumab; Part 2: feladilimab +tremelimumab

Docetaxel DRUG

Docetaxel is a microtubule stabilizer which will be administered as an IV infusion once every 3 weeks at a dose of 75 milligrams per meter square (mg/m\^2).

Part 2: SOC

Paclitaxel DRUG

Paclitaxel is a microtubule stabilizer which will be administered as an IV infusion once weekly at a dose of 80 mg/m\^2.

Part 2: SOC

Cetuximab DRUG

Cetuximab is a recombinant, human/mouse chimeric anti-estimated glomerular filtration rate (EGFR) mAb. Cetuximab will be administered at a loading dose of 400 mg/m\^2 followed by 250 mg/m\^2 once weekly.

Part 2: SOC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
• Male or female, aged 18 years or older.
• Body weight \>=30 kilograms (kg).
• Histological or cytological documentation of an invasive malignancy that was diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the following tumor types: a) Part 1: cutaneous melanoma; HNSCC (oral cavity, larynx, oropharynx, hypopharynx, nasal cavity/paranasal sinuses); non-small cell lung cancer (squamous and non-squamous); urothelial carcinoma of the upper and lower urinary tract; clear cell renal carcinoma; castrate resistant prostate adenocarcinoma. b) Part 2: HNSCC (oral cavity, larynx, pharynx, paranasal sinuses).
• Part 1 only: Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists, or where standard therapy is refused. May be anti-PD-1/anti-PD-L1 experienced or naïve.
• Part 2 only: Disease that has progressed after receiving platinum-based chemotherapy (unless medically contraindicated or discontinued due to toxicity) and anti-PD-1/anti-PD-L1 therapy (in combination or as separate lines of therapy in either sequence).
• Measurable disease per RECIST version 1.1 guidelines. Palpable lesions that are not measurable by radiographic or photographic evaluations may not be utilized as the only measurable lesion. Any measurable lesion biopsied at Screening cannot be followed as a target/index lesion unless agreed upon by GlaxoSmithKline (GSK).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
• Adequate organ function.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions apply: a) Not a woman of childbearing potential (WOCBP); or, b) A WOCBP who agrees to follow the contraceptive while receiving study intervention and for at least 180 days after the last dose of study intervention.
• A male subject must agree to use a highly effective contraception while receiving study intervention and for at least 180 days after the last dose of study intervention and refrain from donating sperm during this period.
• Agree to collection of tumor tissue: a) Part 1 and Part 2: Archival tumor tissue collected any time from the initial diagnosis of invasive malignancy; a fresh tumor biopsy will be required if archival specimen is unavailable prior to first dose. b) Part 1 pharmacokinetic/pharmacodynamic cohort(s): Archival tissue as noted in point (a) above. Paired tumor biopsies: tumor tissue collected any time after completion of dosing of the last therapy and prior to first dose and an on-treatment biopsy. c) Part 2: A minimum of 15 subjects from each arm will be required to provide paired tumor biopsies (in addition to the archival tissues as noted in point (a) above): tumor tissue collected any time after completion of dosing of the last therapy and prior to first dose and an on-treatment biopsy.

You may not qualify if:

• Received prior treatment with the following therapies; calculation is based on date of last therapy to date of first dose of study intervention or SOC: a) Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4 \[including tremelimumab\] or Inducible T Cell Co-Stimulator (ICOS)-directed therapies at any time; b) \>=4 lines of prior anticancer treatment: In subjects that relapse or progress within 1 year from the beginning of adjuvant or concurrent therapy, the adjuvant/concurrent therapy is considered first line therapy; c) Systemic anticancer therapy or investigational therapy within 30 days, or 5 half-lives, whichever is shorter; at least 14 days must have elapsed between the date of the last prior therapy to the date of first dose of study intervention or SOC.
• Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is available for assessment per RECIST v1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. At least 14 days must have elapsed between the date of the last dosage of radiation and the first dose of study intervention/SOC.
• Invasive malignancy or history of invasive malignancy other than disease under study within the last two years, except: a) Any other invasive malignancy for which the subject was definitively treated, has been disease-free for \<=2 years and in the opinion of the Investigator and Medical Monitor will not affect the evaluation of the effects of the study intervention or SOC on the currently targeted malignancy, may be included in this clinical study; Curatively treated non-melanoma skin cancer or successfully treated in-situ carcinoma.
• Toxicity from previous anticancer treatment that includes: a) \>=Grade 3 toxicity considered related to prior immunotherapy and that led to treatment discontinuation; b) Toxicity related to prior treatment that has not resolved to \<=Grade 1 (except alopecia, vitiligo, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be \<=Grade 2).
• Central nervous system (CNS) metastases, with the following exception: Subjects with previously treated CNS metastases who are clinically stable and had no requirement for steroids during at least 14 days prior to first dose of study intervention or SOC.
• Major surgery \<=28 days of first dose of study intervention or SOC.
• Autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years. Replacement therapies which include physiological doses of corticosteroids for treatment of endocrinopathies (i.e., adrenal insufficiency) are not considered systemic treatments.
• Recent history (within 24 weeks) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess.
• Receiving systemic steroids (\>=10 milligrams \[mg\] oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to first dose of study intervention or SOC.
• Prior allogeneic/autologous bone marrow or solid organ transplantation.
• Received live-virus vaccine within 30 days from start of study intervention or SOC.
• Current or history of idiopathic pulmonary fibrosis, pneumonitis (for past, subject is excluded if steroids were required), interstitial lung disease or organizing pneumonia.
• Recent history (within 24 weeks) of uncontrolled, symptomatic ascites, pleural or pericardial effusions.
• History or evidence of cardiac abnormalities within the 24 weeks prior to enrollment which include: a) Serious uncontrolled cardiac arrhythmia or clinically significant electrocardiogram abnormalities including second degree (Type II) or third degree atrioventricular block. b) Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting. c) Symptomatic pericarditis.
• Current unstable liver or biliary disease per Investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• MedImmune LLC: collaborator

Study Sites (8)

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

New York, New York, 10016-4744, United States

Location

GSK Investigational Site

New York, New York, 10032, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15232, United States

Location

GSK Investigational Site

San Antonio, Texas, 78229, United States

Location

GSK Investigational Site

Melbourne, Victoria, 3000, Australia

Location

GSK Investigational Site

Ottawa, Ontario, K1H 8L6, Canada

Location

GSK Investigational Site

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• Hilton JF, Ott PA, Hansen AR, Li Z, Mathew M, Messina CH, Dave V, Ji X, Karpinich NO, Hirschfeld S, Ballas M, Zandberg DP. INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors. Cancer Immunol Immunother. 2024 Feb 13;73(3):44. doi: 10.1007/s00262-023-03623-z.

  PMID: 38349570 BACKGROUND

MeSH Terms

Conditions

Neoplasms; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Non-Small-Cell Lung; Melanoma; Carcinoma, Renal Cell

Interventions

tremelimumab; Docetaxel; Paclitaxel; Cetuximab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms by Site; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The sponsor made the decision to not continue the study at the end of Part 1 based on the totality of available data due to lack of efficacy and not due to safety. Hence Part 2 was not initiated and participants were not enrolled in the same.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In Part 1, dose escalation will occur using a zone based approach. Part 2 will be randomized, parallel group study wherein the subjects will be randomized in a ratio of 2:1 to either recommended Phase 2 dose combination of GSK3359609 and tremelimumab or SOC (paclitaxel, docetaxel or cetuximab).

Study Record Dates

• First Submitted: October 1, 2018
• First Posted: October 3, 2018
• Study Start: November 26, 2018
• Primary Completion: June 25, 2021
• Study Completion: September 16, 2021
• Last Updated: August 28, 2024
• Results First Posted: August 22, 2022

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Anonymized IPD is made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.

Locations

US (5); AU (1); CA (2)