A Phase I, Multi-center, Open Label First-in-Human Study With ABBV-CLS-484 Alone and in Combination in Subjects With Locally Advanced or Metastatic Tumors

Study Identifier:
M20-431
CT.gov Identifier:
NCT04777994
EudraCT Identifier:
202350756838
EU Trial (CTIS) Number:
2023-507568-38-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

To  assess the safety, PK, PD, and preliminary efficacy of ABBV-CLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI).

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Solid Tumor
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I
Sex
Female & Male
Age
18+ years
Study Drug
Drug: Experimental: Monotherapy Dose Escalation
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Drug: Intervention:
Drug: Experimental: Combination Dose Escalation with PD-1 Inhibitor
Drug: Drug: Programmed Cell Death-1 (PD-1) Inhibitor
Drug: Drug: ABBV-CLS-484
Drug: Experimental: Combination Dose Escalation with VEGFR TKI
Drug: Drug: Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitor (TKI)
Drug: Experimental: Combination Expansion
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Must weigh at least 35 kilograms (kg).
  • An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  • Life expectancy of ≥ 12 weeks.
  • Laboratory values meeting protocol criteria.
  • QT interval corrected for heart rate < 470 msec (using Fridericia's correction), and no clinically significant electrocardiographic findings.
  • Measurable disease defined by RECIST 1.1 criteria.
  • For Monotherapy and Combination Dose Escalation:
  • • Subjects with histologically or cytologically proven metastatic or locally advanced tumors, for which no effective standard therapy exists, or where standard therapy has failed. Subjects must have received at least 1 prior systemic anticancer therapy for the indication being considered.
  • For Monotherapy Dose Expansion only:
  • Subjects must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with a best response by RECIST v1.1 of CR/PR/stable (any duration) or stable disease (for greater than 6 months); AND
  • Must have been previously treated with 1 or more prior lines of therapy in the locally advanced or metastatic setting with the following tumor types:
  • Relapsed/refractory HNSCC
  • Relapsed/refractory NSCLC
  • Advanced ccRCC
  • For PD-1 Targeting Agent Combination Dose Expansion only:
  • For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with response by RECIST v1.1 of CR/PR (any duration) or stable disease (for greater than 6 months):
  • Relapsed HNSCC
  • Relapsed NSCLC
  • Relapsed Advanced ccRCC
  • For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy and have had disease progression with PD-1/PD-L1 targeted therapy:
  • Locally Advanced or metastatic MSI-H tumors
  • For VEGFR TKI Combination Dose Expansion only:
  • Relapsed advance ccRCC with no more than 1 prior VEGFR TKI
  • Subjects no recent history of hemorrhage, including hemoptysis, hematemesis, or melena
  • Subjects with poorly controlled hypertension are excluded Adult subjects weighing at least 35 kg who meet the following key eligibility criteria will be enrolled:
  • For Monotherapy and Combination Dose Escalation: Subjects with histologically or cytologically proven metastatic or locally advanced tumors, for which no effective standard therapy exists, or where standard therapy has failed. Subjects must have received at least 1 prior systemic anticancer therapy for the indication being considered. Specific criteria are required depending on enrollment cohort.
  • For Monotherapy HNSCC Dose Expansion only: Subjects with relapsed/refractory HNSCC who have received 1-3 prior lines of therapy (and no more than 1 prior line containing PD-1/PD-L1 targeted therapy) whose tumors express PD-L1 (combined positive score [CPS] >= 1) as determined by the Food and Drug Administration (FDA)-approved PD-L1 immunohistochemistry (IHC) assays.a
  • For Monotherapy and Pembrolizumab Combination ccRCC Dose Expansions only: Subjects with advanced ccRCC who must have been previously treated with at least 1 prior line of therapy (and no more than 1 prior line containing PD-1/PD-L1 targeted therapy) in the locally advanced or metastatic setting.
  • For Pembrolizumab Combination NSCLC and MSI-H Dose Expansion only: For the following tumor types, subjects must have received at least 1 prior line of therapy (and no more than 1 prior line containing PD-1/PD-L1 targeted therapy):
  • -NSCLC(outcome of prior PD-1/PD-L1 targeted therapy: relapsed), tumors express PD-L1 (TPS>=1%)a
  • -NSCLC(outcome of prior PD-1/PD-L1 targeted therapy: refractory), tumors express PD-L1 (TPS>=1%)a
  • -MSI-H tumors(outcome of prior PD-1/PD-L1 targeted therapy: refractory), Locally advanced or metastatic MSI-H tumors whose tumors are determined to have a MSI-H status by PCR or NGS tests, or dMMR by IHC tests.
  • a. Prior PD-L1 test results per Agilent PD-L1 22C3 (preferred), Ventana PD-L1 SP142, Ventana SP263 or Dako 28-8 IHC assays are acceptable. PD-L1 positivity must be determined prior to enrollment. If PD-L1 IHC assay results are not available, the subjects tumor tissue samples must be tested at designated local or sponsor approved central lab for PD-L1 status prior to enrollment.
  • Note: Relapsed from prior PD-1/PD-L1 therapy is defined as the subject having received at least 1 prior line containing PD-1/PD-L1 targeted therapy with a best response by RECIST v1.1 of CR/PR (any duration) or stable disease (for greater than 6 months)
  • Refractory to PD-1/PD-L1 therapy is defined as having received at least 1 prior line containing PD-1/PD-L1 targeted therapy and have had disease progression (in the absence of best response of CR/PR/stable disease by RECIST v1.1) with PD-1/PD-L1 targeted therapy.
  • For Cabozantinib Combination Dose Expansion only:
  • -Subjects with locally advanced or metastatic, advanced ccRCC who have relapsed after no more than 1 prior VEGFR TKI therapy with a best response of CR/PR/stable disease by RECIST v1.1.
  • -Subjects with no recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
  • -Subjects must not have discontinued cabozantinib due to related toxicity when administered as monotherapy or in combination in previous line(s) of treatment.
  • -Subjects with known hypersensitivity reaction to active ingredients or other ingredients of cabozantinib are excluded.
  • -Subjects with known hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption (since cabozantinib formulation contains lactose) are excluded.
  • -Subjects with poorly controlled hypertension are excluded
  • Measurable disease defined by RECIST 1.1 criteria.
  • An Eastern Cooperative Oncology Group (ECOG) performance status <= 2
  • Life expectancy of >= 12-weeks
  • Laboratory values meeting the following criteria within the screening period and prior to the first dose of study drug:
  • -Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2 x the upper limit of normal (ULN).
  • -Total bilirubin <= 1.5 x ULN. Subjects with Gilberts syndrome may have total bilirubin <3 x ULN if direct bilirubin is within normal limits.
  • -Renal clearance as estimated glomerular filtration rate by modification of diet in renal disease (MDRD) (using the National Institute of Health [NIH] National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] calculator) or measured by 24-hour urine collection of >= 50 mL/min/1.73 m2, or another validated method.
  • -Absolute neutrophil count >= 1,500/mm3 (with no granulocyte-colony stimulating factor) within 21 days.
  • -Platelet count >= 100,000/uL (with no platelet transfusion within 7 days).
  • -Hemoglobin >= 9 g/dL (with no red blood cell transfusion within 14 days).
  • -International normalized ratio, prothrombin time, or activated partial thromboplastin time <= 1.5 x ULN unless on anticoagulant therapy. If the subject is on anticoagulant therapy, INR must be within therapeutic goal.
  • QT interval corrected for heart rate (QTc) < 470 msec (using Fridericia's correction), and no clinically significant electrocardiographic findings.
  • No untreated brain or meningeal metastases (i.e., subjects with history of metastases are eligible provided they do not require ongoing steroid treatment and have shown clinical and radiographic stability for at least 28 days on 10 mg or less of steroides after definitive therapy).
  • No unresolved Grade 2 or higher toxicities related to previous anticancer therapy except alopecia and hypothyroidism that is well controlled with medications.
  • No unresolved Grade 2 or higher peripheral neuropathy.
  • No history of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
  • No recent history (within 6 months) of congestive heart failure (defined as New York Heart Association, Class 2 or higher), ischemic cardiovascular event, pericarditis, or clinically significant pericardial effusion or arrythmia.
  • No recent history (within 6 months) of Childs-Pugh B or C classification of liver disease.
  • No history of clinically significant medical and/or psychiatric conditions or any other reason that, in the opinion of the investigator, would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
  • No history of uncontrolled, clinically significant endocrinopathy.
Exclusion criteria
  • Untreated brain or meningeal metastases (i.e., subjects with history of metastases are eligible provided they do not require ongoing steroid treatment and have shown clinical and radiographic stability for at least 28 days after definitive therapy)
  • Unresolved Grade 2 or higher toxicities related to previous anticancer therapy except alopecia.
  • Unresolved Grade 2 or higher peripheral neuropathy.
  • History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
  • Recent history (within 6 months) of congestive heart failure (defined as New York Heart Association, Class 2 or higher), ischemic cardiovascular event, pericarditis, or clinically significant pericardial effusion or arrythmia.
  • Recent history (within 6 months) of Childs-Pugh B or C classification of liver disease.
  • History of clinically significant medical and/or psychiatric conditions or any other reason that, in the opinion of the investigator, would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
  • History of uncontrolled, clinically significant endocrinopathy.
  • Known gastrointestinal disorders making absorption of oral medications problematic; subject must be able to swallow capsules.
  • If treated with a PD-1/aPD-L1 targeting or other immune-oncology agents in the past, excluded if had prior pneumonitis, prior Grade 3 or higher immune mediated toxicity, hypersensitivity to administered drug or drug related toxicity requiring discontinuation.
  • Active autoimmune disease requiring systemic treatment in past 2-years (exceptions for endocrinopathies, vitiligo or atopic conditions).
  • History of solid organ transplant or allogeneic stem cell transplant.
  • History of other malignancy, with the following exceptions:
  • No known active disease present for > or = 3 years before first dose of study treatment and felt to be at low recurrence by investigator.
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ without evidence of disease.
  • History of interstitial lung disease or pneumonitis.
  • Major surgery < or = 28 days prior to first dose of study drug
  • Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local testing practices. Subject must not have known gastrointestinal disorders making absorption of oral medications problematic.
  • If treated with anti-PD-1/anti-PD-L1 targeting or other immunostimulatory agents in the past: excluded if had prior pneumonitis, prior Grade 3 or higher immune mediated toxicity, Grade 3 or higher hypersensitivity to administered drug or drug related toxicity requiring discontinuation. Exceptions to this
  • exclusion criterion include the following:
  • -Patients with a history of immune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
  • -Patients with immune-related controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
  • -Patients with immune-related controlled adrenal insufficiency on stable doses of hormone replacement may be eligible
  • -Patients with immune-related controlled hypophysitis on stable doses of hormone replacement may be eligible.
  • Subject must not have an active autoimmune disease requiring systemic immunosuppressive treatment in past 2-years (exceptions for endocrinopathies, vitiligo or atopic conditions).
  • Subject must not have history of solid organ transplant or allogeneic stem cell transplant.
  • Subject must not have history of or ongoing interstitial lung disease or pneumonitis.
  • Subject must not have had major surgery <= 28 days prior to first dose of study drug.
  • No history of other malignancy, with the following exceptions:
  • -No known active disease present within 3 years before first dose of study treatment. For subjects with history of other malignancy beyond 3 years, must be felt to be at low risk of recurrence by investigator.
  • -Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  • -Adequately treated carcinoma in situ without evidence of disease.
  • No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local testing practices.
  • Must not have been treated with any investigational drug or systemic anticancer treatments within 28 days or 5 half-lives of the drug (whichever is shorter) before the first dose of study drug or is currently enrolled in another clinical study.
  • Must not have been previously treated with PTPN2/N1 inhibitors.
  • Must not have been treated with steroids as anticancer therapy within 7 days before the first dose of study drug.
  • Must not have systemically used known OAT3 inhibitors or MATE1/2-K inhibitors within 7 days before the first dose of study drug and throughout the first cycle.
  • Must not have systemically used medications known to prolong the QT interval for at least 5 half-lives of the medication or 14 days (whichever is shorter) before the first dose of study drug and throughout Cycle 1.
  • Must not have received any live vaccine within 28 days before the first dose of study drug or be expected to need a live vaccination during study participation including at least 28 days after the last dose of study drug.
  • Must not have used immunosuppressive medications within 14 days of first dose of study drug. Physiologic doses of corticosteroids allowed.
  • Palliative radiation or palliative surgery will be allowed if the subject is otherwise stable.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Emiliano Calvo
Status
Recruiting
Condition(s) Treated at Site
Solid Tumor