NCT03881488 · REGISTRY CONDITION SEARCH

Study of CTX-471 as a Monotherapy or in Combination With Pembrolizumab in Patients Post PD-1/PD-L1 Inhibitors in Metastatic or Locally Advanced Malignancies

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1
Status at capture: TERMINATED
Registry last update: 2026-10-09

This is a Phase 1, open-label, first-in-human study of CTX-471 administered as a monotherapy or in combination with pembrolizumab in patients with metastatic or locally advanced malignancies that have progressed while receiving an approved PD-1 or PD-L1 inhibitor. The study will be conducted in 2 treatment arms (Monotherapy Arm 1 and Combination Arm 2). Each arm will have two parts: Part 1 Dose Escalation and Part 2 Dose Expansion. In each arm (monotherapy and combination therapy), data from Part 1 (dose escalation) and Part 2 (dose expansion) were combined by dose level for reporting.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Participants With Dose Limiting Toxicities (DLTs), Treatment-emergent Adverse Events (TEAEs), and/or Changes in Clinical Laboratory Abnormalities

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outcome · POSTED

Maximum Serum Concentration (Cmax) of CTX-471

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outcome · POSTED

Area Under the Serum Concentrations of CTX-471 Versus Time Curve (AUC)

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outcome · POSTED

Half-life (t1/2) of Serum Concentration of CTX-471

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outcome · POSTED

Development of Anti-drug Antibodies

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outcome · POSTED

Overall Response Rate

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outcome · POSTED

Duration of Response

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outcome · POSTED

Progression-free Survival

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outcome · POSTED

Overall Survival

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: 1. Age 18 years or older 2. Histologically confirmed diagnosis: 1. Monotherapy Arm 1 ( Part 1 and 2): metastatic or locally advanced malignancies 2. Combination Arm 2 Par 1 Dose Escalation: metastatic or locally advanced non-small cell lung, small cell lung cancer, mesothelioma, melanoma, or head and neck cancer 3. Combination Arm 2 Part 2 Dose Expansion: metastatic or locally advanced non-small cell lung, small cell lung cancer, or melanoma 3. Measurable disease per RECIST 1.1 4. Disease progression after at least 12 weeks and at least 2 doses of a commercially available PD-1 or PD-L1 inhibitor per approved prescriber's information, whether monotherapy or in combination therapy, with no other intervening systemic anticancer therapy prior to enrollment 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 6. Life expectancy \> 12 weeks 7. Adequate bone marrow function defined by ANC of ≥ 1.5×10\^9/L, platelet count of ≥100.0×10\^9/L, and hemoglobin of ≥ 9.0 g/dL (with or without transfusion) a. For Combination Arm 2: these criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Patients can be on a stable dose of erythropoietin (≥ approximately 3 months) 8. Adequate hepatic function defined as serum total bilirubin \< 1.5 ULN, AST/ALT ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases) 9. Adequate renal function defined as creatinine clearance \> 30 mL/min as determined by the Cockcroft-Gault equation 10. Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be least 2 years postmenopausal or commits to use 2 acceptable forms of birth control (defined as the use of an intrauterine device, a barrier method with spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration of the study and for 4 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 4 months following the last dose of study treatment 11. Female patients who are women of childbearing potential (WCBP) must have a negative serum pregnancy test at Screening within 7 days of dosing with CTX-471 for Monotherapy Arm 1, and within 72 hours of dosing with CTX-471 and pembrolizumab for Combination Arm 2 12. For Monotherapy Arm 1 Only: Last dose of previous PD-1 or PD-L1 therapy ≥ 28 days, other anticancer therapy \> 21 days (or 2 half-lives for proteins, whichever is longer), radiotherapy \> 21 days (concurrent localized palliative radiotherapy is allowed during CTX-471 treatment), or surgical intervention \>21 days prior to the first dose of CTX-471 13. Resolution of all prior anti-cancer therapy toxicities ≤ Grade 1. Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Patients with ≤Grade 2 neuropathy may be eligible. Patients with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. 14. For Monotherapy Arm 1 Only: Willingness to provide pre- and post-treatment fresh tumor biopsies 15. Capable of understanding and complying with protocol requirements 16. Signed and dated institutional review board/independent ethics committee-approved informed consent form before any protocol-directed screening procedures are performed Exclusion Criteria: 1. Developed clinically significant adverse reaction to PD-1 or PD-L1 therapy, including immune related adverse reactions, which led to discontinuation of treatment 2. Prior treatment with other investigational immune-oncology therapies 3. Systemic therapy with immunosuppressive agents within 7 days before the start of CTX-471 treatment. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed 4. Patient is a pregnant or lactating WCBP 5. Prior solid organ transplantation 6. Active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus infection (HIV) or a positive serological test at Screening within 28 days of dosing with CTX 471 1. Participants who are HBsAg (hepatitis B surface antigen) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention 2. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization 3. HIV infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: * Participants on ART must have a CD4+ T-cell count \>350 cells/mm3 at time of screening * Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening * Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1) 7. Active autoimmune disease or medical conditions requiring chronic steroid (ie, \> 10 mg/day prednisone or equivalent) or immunosuppressive therapy. Patients with a prior history of autoimmune disease may be eligible following discussion with the Medical Monitor 8. For Monotherapy Arm 1 Only: History of central nervous system metastases 9. History of seizure disorders 10. Congestive heart failure (\> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or clinically significant cardiac arrhythmias 11. Other systemic conditions or organ abnormalities that in the opinion of the Investigator may interfere with the conduct and/or interpretation of the current study 12. For Combination Arm 2 Only: Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-life drugs) prior to treatment. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement may be eligible Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention 13. For Combination Arm 2 Only: Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease 14. For Combination Arm 2 Only: Has had an allogeneic tissue transplant 15. For Combination Arm 2 Only: Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines are allowed 16. For Combination Arm 2 Only: Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, that have undergone potentially curative therapy are not excluded 17. For Combination Arm 2 Only: Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment 18. For Combination Arm 2 Only: Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients 19. For Combination Arm 2 Only: Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease 20. For Combination Arm 2 Only: Has an active infection requiring systemic therapy 21. For Combination Arm 2 Only: Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator 22. For Combination Arm 2 Only: Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study 23. For Combination Arm 2 Only: Has received radiation therapy to the lung that is \> 30Gy within 6 months of the first dose of trial treatment
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Escalating doses of CTX-471 depending on cohort at enrollment
intervention Names
Drug: CTX-471
label
Arm 1 Part 1 Dose Escalation
type
EXPERIMENTAL
description
Two dose groups of CTX-471 (0.3 mg/kg and 0.6 mg/kg)
intervention Names
Drug: CTX-471
label
Arm 1 Part 2 Dose Expansion
type
EXPERIMENTAL
description
Escalating doses of CTX-471 in combination with pembrolizumab (KEYTRUDA® ) depending on cohort at enrollment
intervention Names
Drug: CTX-471
Drug: Pembrolizumab (KEYTRUDA®)
label
Arm 2 Part 1 Dose Escalation
type
EXPERIMENTAL
description
Two cohorts of CTX-471 (0.3 mg/kg and 0.6 mg/kg) in combination with pembrolizumab (KEYTRUDA® ) (400 mg) in three tumor type subgroups. Cohort 1 - Group 1A - NSCLC , Group 1B -SCLC and Group 1C - Melanoma. Cohort 2 Group 2A - NSCLC, Group 2B - SCLC and Group 2C -Melanoma.
intervention Names
Drug: CTX-471
Drug: Pembrolizumab (KEYTRUDA®)
label
Arm 2 Part 2 Dose Expansion
type
EXPERIMENTAL

interventions

arm Group Labels
Arm 1 Part 1 Dose Escalation
Arm 1 Part 2 Dose Expansion
Arm 2 Part 1 Dose Escalation
Arm 2 Part 2 Dose Expansion
description
IV infusion every 2 weeks
name
CTX-471
type
DRUG
arm Group Labels
Arm 2 Part 1 Dose Escalation
Arm 2 Part 2 Dose Expansion
description
IV infusion every 6 weeks
name
Pembrolizumab (KEYTRUDA®)
other Names
KEYTRUDA®
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SEQUENTIAL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 100
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Hematological and nonhematological DLTs were defined in the protocol. TEAE is an occurrence of an adverse event that started or worsened in severity on or after the first dose of CTX-471. Change in clinical laboratory abnormalities is defined as a TEAE related to laboratory results.
measure
Number of Participants With Dose Limiting Toxicities (DLTs), Treatment-emergent Adverse Events (TEAEs), and/or Changes in Clinical Laboratory Abnormalities
time Frame
From first CTX-471 dose to 4 weeks after first dose for DLTs in monotherapy arms, to 6 weeks after first dose for DLTs in combination arms, to 60 days after last dose for TEAEs and clinical laboratory abnormalities in both monotherapy and combination arms

secondary Outcomes

description
Calculated from plasma concentrations measured from samples collected at times shown below
measure
Maximum Serum Concentration (Cmax) of CTX-471
time Frame
Monotherapy arms: before Week 1 dose; 1, 6, 24 hours and 2 weeks after Week 1 dose; before Week 9 dose; 1, 6, 24 hours and 2 weeks after Week 9 dose. Combination therapy arms: before Week 1 dose; 1, 6, 24 hours and 2 weeks after Week 1 dose.
description
AUC(0-24) = AUC from time 0 to 24 hours (1 day); AUC(0-336) = AUC from time 0 to 336 hours (14 days). Calculated from plasma concentrations measured from samples collected at the time points below.
measure
Area Under the Serum Concentrations of CTX-471 Versus Time Curve (AUC)
time Frame
Monotherapy arms: before Week 1 dose; 1, 6, 24 hours and 2 weeks after Week 1 dose; before Week 9 dose; 1, 6, 24 hours after Week 9 dose. Combination therapy arms: before Week 1 dose; 1, 6, 24 hours and 2 weeks after Week 1 dose.
measure
Half-life (t1/2) of Serum Concentration of CTX-471
time Frame
Calculated from plasma concentrations measured from samples collected before the first dose of CTX-471; 1, 6, and 24 hours after the first dose of CTX-471; and before the second dose of CTX-471 (Weeks 1 to 3)
description
Frequency of patients with a negative test result for antibody to CTX-471 prior to treatment who had a positive test for antibody to CTX-471 after treatment. For monotherapy arms, end of treatment was an average 18 weeks, and 60 days after end of treatment was an average 27 weeks. For combination arms, end of treatment was an average 15 weeks, and 60 days after end of treatment was an average 24 weeks.
measure
Development of Anti-drug Antibodies
time Frame
Monotherapy arms: Weeks 3, 5, 9, 13, 17, 21, 25, 29, 33, and 37 and end of treatment and 60 days after end of treatment; Combination therapy arms: Weeks 5, 9, 13, 19, 25, 31, and 37 and end of treatment and 60 days after end of treatment
description
Percentage of patients whose best overall response to treatment was complete response or partial response (as assessed by Response Evaluation Criteria in Solid Tumours guideline version 1.1)
measure
Overall Response Rate
time Frame
From the first dose of CTX-471 to treatment discontinuation (average of 18 weeks for monotherapy groups and and average of 15 weeks for combination groups)
description
Time period from date of CT or MRI that first confirmed complete or partial response to date of CT or MRI that first confirmed progression of disease (as assessed by Response Evaluation Criteria in Solid Tumours guideline version 1.1)
measure
Duration of Response
time Frame
From first date of complete or partial response to first date of disease progression or death
description
Time from the first dose of CTX-471 to disease progression (as assessed by Response Evaluation Criteria in Solid Tumours guideline version 1.1) or death
measure
Progression-free Survival
time Frame
From the first dose of CTX-471 to progression of disease or death
description
Time from the first dose of CTX-471 to death
measure
Overall Survival
time Frame
From the first dose of CTX-471 to death

Full study description

brief Summary: This is a Phase 1, open-label, first-in-human study of CTX-471 administered as a monotherapy or in combination with pembrolizumab in patients with metastatic or locally advanced malignancies that have progressed while receiving an approved PD-1 or PD-L1 inhibitor. The study will be conducted in 2 treatment arms (Monotherapy Arm 1 and Combination Arm 2). Each arm will have two parts: Part 1 Dose Escalation and Part 2 Dose Expansion. In each arm (monotherapy and combination therapy), data from Part 1 (dose escalation) and Part 2 (dose expansion) were combined by dose level for reporting.

Source references

references

citation
Singh R, Kim YH, Lee SJ, Eom HS, Choi BK. 4-1BB immunotherapy: advances and hurdles. Exp Mol Med. 2024 Feb;56(1):32-39. doi: 10.1038/s12276-023-01136-4. Epub 2024 Jan 4.
pmid
38172595
type
DERIVED

Source notices and limitations

Discovery and provenance

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Preserved source evidence · Not medical advice