Phase II Umbrella Study of Novel Anti-cancer Agents in Participants With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy

Phase 2Active Not RecruitingNCT03334617

AstraZeneca528 enrolled

Overview

This is an open-label, multi-centre, umbrella Phase II study in participants with metastatic NSCLC who have progressed on an anti-PD-1/PD-L1 containing therapy. This study is modular in design, allowing initial assessment of the efficacy, safety, and tolerability of multiple treatment arms.

This is an open-label, multi-centre, umbrella Phase II study in participants with metastatic non-small cell lung cancer (NSCLC) who have progressed on an anti-programmed cell death-1/anti-programmed cell death ligand 1 (anti-PD-1/PD-L1) containing therapy. This study is modular in design, consisting of a number of treatment cohorts, allowing evaluation of the efficacy, safety, and tolerability of multiple treatment arms. There is currently no established therapy for participants who have received immune checkpoint inhibitors and platinum-doublet therapies, and novel treatments are urgently needed. This protocol has a modular design, with the potential for future treatment arms to be added via protocol amendment.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

528

Conditions

Non-Small Cell Lung Cancer

Interventions

DurvalumabDRUG

Participants will receive IV infusion of durvalumab as stated in arm description.

DanvatirsenDRUG

Participants will receive IV infusion of danvatirsen as stated in arm description.

CeralasertibDRUG

Participants will receive oral tablet of ceralasertib as stated in arm description.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

Inclusion criteria: * At least 18 years of age at the time of signing the informed consent form. * Participant must have histologically or cytologically confirmed metastatic or locally advanced and recurrent non-small-cell lung cancer (NSCLC) which is progressing. * Participants eligible for second- or later-line therapy, who must have received an anti-programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) containing therapy and a platinum-doublet regimen for locally advanced or metastatic NSCLC either separately or in combination. Prior durvalumab is acceptable. The participant must have had disease progression on a prior line of anti-PD-1/PD-L1 therapy. * Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance status of 0 to 1, and a minimum life expectancy of 12 weeks. * Participant must have at least 1 lesion that can be accurately measured. A previously irradiated lesion can be considered a target lesion if the lesion has clearly progressed. * Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal participants. Exclusion Criteria: * Participants whose tumour samples have targetable alterations in epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) at initial diagnosis are excluded. In addition, participants whose tumour samples are known to have targetable alterations in ROS1, BRAF, MET or RET, are to be excluded. * Active or prior documented autoimmune or inflammatory disorders. * Active infection including tuberculosis, hepatitis B (known positive hepatitis B virus \[HBV\] surface antigen \[HBsAg\] result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus \[HIV\] 1/2 antibodies). * Female participant who are pregnant or breastfeeding, or male or female participants of reproductive potential who are not willing to employ effective birth control. * Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients, or history of severe hypersensitivity reactions to other monoclonal antibodies. * Participant has spinal cord compression or symptomatic brain metastases. * Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Participants may receive treatment with bisphosphonates or receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors for the treatment of bone metastases. * History of active primary immunodeficiency.

Locations (45)

Outcomes

Primary Outcomes

Percentage of Participants With Objective Response Per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1)

Objective response was defined as participants with a confirmed investigator-assessed response complete response (CR) or partial response (PR) based on RECIST v 1.1. The CR is defined as disappearance of all target (TL) and non-target lesions (NTL), and any pathological lymph node (whether target or nontarget) must have reduction in short axis to \<10 mm. The PR is defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum diameters, as long as criteria for progressive disease (PD) are not met. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from date of first documentation. Percentage of participants with objective response was reported.

Time frame: Baseline (<=28 days before treatment), then every 6 weeks for 24 weeks from Cycle 1 Day 1, then every 8 weeks (every 9 weeks in Module 6) until disease progression or 90 days after study drug discontinuation (approximately 2 years)

Secondary Outcomes

Overall Survival (OS)

The OS is defined as the time from the first dose of any study drug until death due to any cause regardless of whether the participant withdraws from study treatment or receives subsequent cancer therapy. The overall survival was analyzed using the Kaplan-Meier method.

Time frame: Every 3 months after safety follow-up visit (90 days after study drug discontinuation) until planned database lock for a module (either 12 months after last participant has started treatment or when 75% of participants died) (approximately up to 2 years)

Progression-Free Survival (PFS) Per RECIST v1.1

The PFS is defined as time from first dose of any study drug until date of objective disease progression (PD) per RECIST v1.1 or death by any cause, regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression. The PD is defined as a \>= 20% increase in the sum of diameters of TLs and an absolute increase of \>= 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or unequivocal progression of existing NTL. The PFS was analyzed using the Kaplan-Meier method

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Participants will receive oral tablets of vistusertib as stated in arm description.

OlaparibDRUG

Participants will receive oral tablets of olaparib as stated in arm description.

OleclumabDRUG

Participants will receive IV infusion of oleclumab as stated in arm description.

Trastuzumab deruxtecanDRUG

Participants will receive IV infusion of trastuzumab deruxtecan as stated in arm description.

CediranibDRUG

Participants will receive oral tablets of cediranib as stated in arm description.

Research Site

Duarte, California, United States

Research Site

Fullerton, California, United States

Research Site

La Jolla, California, United States

Research Site

Los Angeles, California, United States

Research Site

Washington D.C., District of Columbia, United States

Research Site

Chicago, Illinois, United States

Research Site

Baltimore, Maryland, United States

Research Site

Baltimore, Maryland, United States

Research Site

Boston, Massachusetts, United States

Research Site

St Louis, Missouri, United States

...and 35 more locations

Best Percentage Change From Baseline in Tumour Size

The best percentage change in tumour size from baseline i.e. the maximum reduction from baseline or the minimum increase from baseline in absence of a reduction from baseline based on all post baseline assessments is reported. Tumour size is sum of the longest diameters (or short axis measurements for lymph nodes) of the target lesions. Baseline was defined as last evaluable assessment prior to starting treatment. The percentage change in target lesion tumour size at each week X for which data are available was obtained for each participant taking the difference between the sum of the target lesions at each week X and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline multiplied by 100 (i.e. \[week X - baseline\]/baseline \* 100).

Time frame: Baseline (<=28 days prior to starting treatment) then every 6 weeks for first 24 weeks relative to the date of first dose/combination therapy (Cycle 1 Day 1), then every 8 weeks (except Module 6)/9 weeks (Module 6) thereafter (approximately up to 2 years)

Percentage of Participants With Disease Control (DC) Per RECIST v1.1

Module (M) 1, 4, 5, 6, 7, 8, 9, 11: DCR at 12 and 24 weeks is defined as percentage of participants who have best overall response (BoR) of CR or PR in first 13/25 weeks, respectively, post start of any study drug or with duration of SD for at least 11/23 weeks, respectively, after start of any study drug. M2, M3, M10: DCR at 12 and 24 weeks is defined as percentage of participants who have BoR of CR or PR within first 100 days (M2, M3, M10) or 184 days (M2, M3, M10) after start of any study drug, or have SD lasting at least 86 days (M2)/82 days (M3, M10), respectively, or 170 days (M2)/166 days (M3, M10), respectively, post start of any study drug. CR is defined as disappearance of all TL and NTLs, and any pathological lymph node (whether target or nontarget) must have reduction in short axis to \<10 mm. PR is defined as at least 30% decrease in sum of diameters of TLs, taking as reference baseline sum diameters, as long as criteria for PD are not met.

Time frame: At 12 and 24 weeks after the start of study drug

Duration of Response (DoR) Per RECIST v1.1

The DoR is defined as the time from the first documented confirmed response (CR or PR) until the first documented PD or death in the absence of disease progression. The CR is defined as disappearance of all TLs and NTLs, and any pathological lymph node (whether target or nontarget) must have reduction in short axis to \<10 mm. The PR is defined as at least a 30 decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters, as long as criteria for PD are not met. The PD is defined as a \>=20% increase in the sum of diameters of TLs and an absolute increase of \>=5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters, or unequivocal progression of existing NTL. The DoR was analyzed using the Kaplan-Meier method.

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.