Trial: Ph1b/2 Study of the Safety and Efficacy…

Trial Details

Sponsor: AstraZeneca (industry)

Phase: 2

Start date: June 3, 2020

Planned enrollment: 413

Trial ID: NCT04379596

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Volrustomig (MEDI5752, PD-1/CTLA-4 DuetMab, MEDI-5752)

Overview

Volrustomig, also known as MEDI5752 or PD-1/CTLA-4 DuetMab, is an investigational bispecific monoclonal antibody targeting both PD-1 and CTLA-4 immune checkpoints. It is designed to fully inhibit PD-1 while preferentially inhibiting CTLA-4 on activated PD-1–positive T cells, aiming to enhance antitumor immune responses. (oncologypro.esmo.org)

Mechanism of Action

Volrustomig's bispecific nature allows it to simultaneously block PD-1 and CTLA-4 pathways. This dual inhibition is intended to restore and amplify T-cell activity against tumor cells, potentially leading to improved therapeutic outcomes compared to targeting either checkpoint alone. (aacrjournals.org)

Efficacy

In a Phase 1 study involving treatment-naïve patients with advanced clear cell renal cell carcinoma (ccRCC), volrustomig demonstrated promising efficacy:

750 mg dose cohort (V750):
Objective response rate (ORR): 48.4%
Complete response (CR) rate: 9.7%
Disease control rate (DCR): 90.3%
Median duration of response (DOR): 17.0 months
Median progression-free survival (PFS): 12.3 months
500 mg dose cohort (V500):
ORR: 45.5%
CR rate: 6.1%
DCR: 69.7%
Median DOR: 11.5 months
Median PFS: 9.7 months

These results suggest that volrustomig has the potential to improve outcomes in patients with advanced RCC. (onclive.com)

Safety

The safety profile of volrustomig is consistent with dual checkpoint inhibition:

750 mg dose cohort (V750):
Treatment-related adverse events (TRAEs) occurred in 96.9% of patients, with grade 3 or 4 TRAEs in 62.5%.
Common TRAEs included pruritus (50%), hyperthyroidism (34.4%), and diarrhea (25%).
46.9% of patients discontinued treatment due to TRAEs.
500 mg dose cohort (V500):
TRAEs occurred in 93.9% of patients, with grade 3 or 4 TRAEs in 42.4%.
Common TRAEs included pruritus (39.4%), hyperthyroidism (21.2%), and diarrhea (21.2%).
30.4% of patients discontinued treatment due to TRAEs.

One treatment-related death occurred in the V500 cohort due to bronchopulmonary aspergillosis with immune neutropenia. (onclive.com)

Show for: Rilvegostomig (AZD2936)

HealthScout AI Analysis

Goal: Evaluate safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of trastuzumab deruxtecan (T-DXd) as monotherapy and in combinations with chemotherapy and/or immunotherapy in HER2-expressing advanced/metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma, and to identify recommended phase 2 doses and signals of efficacy across HER2-positive and HER2-low settings.

Patients: Adults (≥18 years) with locally advanced unresectable or metastatic adenocarcinoma of the stomach, GEJ, or esophagus with measurable disease by RECIST v1.1. Parts 1, 2, 3A, 4A enroll HER2-positive disease (IHC 3+ or IHC 2+/ISH+); Parts 3B and 4B enroll HER2-low disease (IHC 2+/ISH– or IHC 1+). Part 1 requires prior progression on trastuzumab-based therapy; Parts 2–4 enroll treatment-naive patients in the metastatic/unresectable setting. Adequate organ function required; key exclusions include active/uncontrolled infections, prior or current ILD/pneumonitis, significant effusions requiring drainage, uncontrolled comorbidities, and active CNS metastases.

Design: Multicenter, open-label, randomized, phase 1b/2 dose-escalation and dose-expansion study with multiple experimental arms versus an active-comparator regimen in first-line disease. Approximately 413 participants will be assigned across cohorts evaluating safety in Part 1 and efficacy (confirmed ORR) in Parts 2–4 by RECIST v1.1.

Treatments: Experimental regimens include: T-DXd with 5-fluorouracil; T-DXd with capecitabine; T-DXd with durvalumab; T-DXd with capecitabine and oxaliplatin; T-DXd with 5-FU and durvalumab; T-DXd with capecitabine and durvalumab; T-DXd monotherapy; T-DXd with 5-FU or capecitabine; T-DXd with pembrolizumab ± 5-FU or capecitabine; T-DXd with volrustomig ± 5-FU or capecitabine; T-DXd with rilvegostomig ± 5-FU or capecitabine. The active comparator is trastuzumab plus fluoropyrimidine (5-FU or capecitabine) with a platinum (cisplatin or oxaliplatin), a standard first-line regimen in HER2-positive gastric/GEJ cancer. Trastuzumab deruxtecan is an anti-HER2 antibody–drug conjugate delivering a topoisomerase I inhibitor payload; it has demonstrated substantial activity in HER2-positive gastric cancer post-trastuzumab and in other HER2-expressing tumors, with interstitial lung disease/pneumonitis as an important identified risk. Volrustomig is a monovalent bispecific antibody targeting PD-1 and CTLA-4 with preferential CTLA-4 blockade on PD-1–positive T cells; early-phase studies have shown encouraging responses in solid tumors, including RCC, with dose-dependent immune-related toxicities and a development focus on sub-1500 mg dosing. Rilvegostomig is a bispecific antibody targeting PD-1 and TIGIT with Fc-silenced IgG1; early-phase NSCLC data show acceptable tolerability at a 750 mg Q3W RP2D, evidence of receptor occupancy, and preliminary disease control in a pretreated population. Durvalumab (anti–PD-L1) and pembrolizumab (anti–PD-1) are approved checkpoint inhibitors broadly active across multiple tumor types; here they are combined with T-DXd ± fluoropyrimidines.

Outcomes: Primary endpoints: Part 1 safety and tolerability including AEs/SAEs (CTCAE v5.0), DLTs, and changes in labs, vitals, and ECGs; Parts 2–4 confirmed ORR by investigator per RECIST v1.1. Key secondary endpoints include ORR in Part 1; safety in Parts 2–4; pharmacokinetics for T-DXd, total anti-HER2 antibody, MAAA-1181a, durvalumab, volrustomig, and rilvegostomig; immunogenicity (ADAs) for T-DXd and immunotherapies; efficacy endpoints DoR, DCR, PFS, and OS; and concordance analyses comparing outcomes by local versus central HER2 testing. Safety and PK/ADA assessments extend up to approximately 24 months; efficacy assessments focus on ORR around 12 months with time-to-event endpoints followed up to 24 months.

Burden on patient: High. The multicohort phase 1b/2 design with multiple combination regimens entails frequent clinic visits, intensive safety monitoring, and serial pharmacokinetic and immunogenicity blood draws across several agents. Imaging for response per RECIST will be performed at regular intervals typical of early-phase trials, likely every 6–8 weeks initially. Combination arms with chemotherapy require infusion visits, potential continuous or oral fluoropyrimidine administration, and management of cytotoxic toxicities. Immunotherapy and ADC-related risks, particularly T-DXd–associated ILD/pneumonitis and cytopenias, necessitate close surveillance, additional pulmonary evaluations if symptomatic, and prompt intervention. Travel burden may be substantial due to the need for frequent assessments across the approximately 24-month follow-up period, with possible on-treatment biopsies per site practice and protocol for biomarker analyses.

Eligibility

Show Criteria

Inclusion criteria:

1. Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations

2. Disease Characteristics:

1. Locally advanced, unresectable, or metastatic disease based on most recent imaging

2. For Part 1, 2, 3a, 4a pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results

3. For Part 3b and 4b, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results

3. For Part 1, progression on or after at least one prior trastuzumabcontaining regimen For Part 2, Part 3 and Part 4, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with with HER2-positive (Part 2 and Part 3 \[Arm 3A\] and Part 4 \[Arm 4A\]) or HER2-low (Part 3 \[Arm 3B\] and Part 4 \[Arm 4B\])) status

4. Has measurable target disease assessed by the Investigator based on RECIST version 1.1

5. Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function

6. If of reproductive potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study.

Exclusion criteria:

1. History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C infection.

2. Uncontrolled intercurrent illness

3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.

4. Lung-specific intercurrent clinically significant severe illnesses.

5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.

6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Volrustomig (MEDI5752, PD-1/CTLA-4 DuetMab, MEDI-5752)

Overview

Mechanism of Action

Efficacy

Safety

Further Reading

Show for: Rilvegostomig (AZD2936)

Overview

Mechanism of Action

Efficacy

Safety

Further Reading

HealthScout AI Analysis

Eligibility

Show Criteria

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