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 (MEDI5752) is an investigational, humanized, monovalent bispecific IgG1 antibody that targets PD‑1 and CTLA‑4. It is being studied across multiple tumor types, including renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), pleural mesothelioma, hepatobiliary cancers, and head and neck cancer, in phases 1–3. Early clinical data show antitumor activity, with ongoing efforts to optimize dose to balance efficacy and immune‑related toxicities. (aacrjournals.org)

Mechanism of action

Volrustomig binds PD‑1 and CTLA‑4 with a “DuetMab” monovalent bispecific format engineered to fully block PD‑1 while preferentially inhibiting CTLA‑4 on activated PD‑1–positive T cells within tumors. This design enhances CTLA‑4 engagement in the tumor microenvironment and reduces activity on PD‑1–negative peripheral T cells. Tethering CTLA‑4 to PD‑1 also drives rapid internalization and degradation of PD‑1, providing a distinct mechanism from conventional separate PD‑1 and CTLA‑4 monoclonal antibodies. The Fc region is engineered to reduce effector function. (aacrjournals.org)

Efficacy

Advanced clear‑cell RCC (first‑line, monotherapy): In a phase 1 expansion (NCT03530397), volrustomig 1,500 mg Q3W produced an ORR of 38.5% in all expansion patients (n=26) and 58.3% in the first‑line ccRCC subset (n=12); median duration of response, PFS, and OS were not reached at 14.6 months’ follow‑up in the first‑line subset. Subsequent first‑line cohorts tested lower fixed doses. At ESMO 2023, ORR was 46.9% with 750 mg (n=32) and 45.5% with 500 mg (n=33); complete responses 9.4% and 6.1%, respectively; median PFS 11.1 and 9.9 months. (ascopubs.org)
Metastatic non‑squamous NSCLC (first‑line, with chemotherapy): In ESMO 2022 LBA56 (phase 1b/2, NCT03530397), volrustomig 1,500 mg + carboplatin/pemetrexed improved median PFS (15.1 vs 8.9 mo), DOR (20.5 vs 9.9 mo), and OS (not reached vs 16.5 mo) versus pembrolizumab + chemotherapy in a small randomized signal‑finding cohort (n=41). A separate single‑arm cohort using 750 mg + chemotherapy showed emerging ORR 44% overall and 48% in PD‑L1 <1% with improved tolerability at ~3.9 months’ follow‑up. A phase 3 trial (eVOLVE‑Lung02) is comparing volrustomig + chemotherapy vs pembrolizumab + chemotherapy in PD‑L1 <50% mNSCLC. (oncologypro.esmo.org)
Ongoing phase 3 programs: Volrustomig + carboplatin/pemetrexed is being compared against platinum/pemetrexed or nivolumab/ipilimumab in unresectable pleural mesothelioma; additional phase 3 evaluation is underway as consolidation after chemoradiotherapy in locally advanced head and neck squamous cell carcinoma. Results are pending. (mayo.edu)
Other tumor settings under study: Master protocols include combinations in hepatocellular and biliary tract cancers (e.g., volrustomig ± bevacizumab or lenvatinib; volrustomig + gemcitabine/cisplatin). RCC combinations with VEGF‑TKIs (e.g., lenvatinib/axitinib) are also in early‑phase evaluation. (mskcc.org)

Safety

Class‑consistent immune‑related adverse events (irAEs) occur and increase with higher dosing/intensity of CTLA‑4 engagement. In RCC expansion at 1,500 mg Q3W, grade 3–4 treatment‑related AEs occurred in 74.1% with discontinuations in 70.4%; hepatotoxicity was a common reason for discontinuation. In the dose‑escalation/expansion RCC cohorts overall, grade 5 TRAEs occurred in 1 patient per cohort. (ascopubs.org)
In NSCLC (ESMO 2022), volrustomig 1,500 mg + chemotherapy had grade ≥3 TRAEs and discontinuations of 70% each; lowering to 750 mg + chemotherapy reduced grade ≥3 TRAEs to 32% and discontinuations to 20%, while maintaining antitumor activity signals. (oncologypro.esmo.org)
Across first‑line RCC mini‑oral cohorts (ESMO 2023), grade 3–4 immune‑related AEs were more frequent at 750 mg than 500 mg (46.9% vs 24.2%), but most non‑endocrine irAEs resolved and about half did not require steroids; overall disease control remained high. (oncologypro.esmo.org)

Show for: Rilvegostomig (AZD2936)

Overview

Rilvegostomig (AZD2936) is an investigational bispecific monoclonal antibody from AstraZeneca that targets PD‑1 and TIGIT. It is being studied across multiple tumor types, with ongoing phase 3 programs including first‑line metastatic non‑squamous NSCLC (ARTEMIDE‑Lung03), adjuvant biliary tract cancer after resection (ARTEMIDE‑Biliary01), first‑line advanced hepatocellular carcinoma (ARTEMIDE‑HCC01), and first‑line HER2‑positive, PD‑L1–positive gastric/GEJ cancer (ARTEMIDE‑Gastric01). (cdek.pharmacy.purdue.edu)

Mechanism of action

Bispecific IgG1 engineered to bind PD‑1 and TIGIT on the same T cell, aiming to augment antitumor immunity beyond PD‑1 blockade alone. The Fc region carries triple mutations (L234F/L235E/P331S) to reduce Fc‑mediated effector function. (cdek.pharmacy.purdue.edu)
Constructed on a DuetMab backbone; the TIGIT arm derives from Compugen’s anti‑TIGIT antibody (COM902). (cdek.pharmacy.purdue.edu)
Early clinical and translational work suggests high receptor occupancy on peripheral T cells at clinically relevant doses. (pmc.ncbi.nlm.nih.gov)

Efficacy

NSCLC (ARTEMIDE‑01, Phase I/II)

CPI‑pretreated cohort (dose escalation/expansion; PD‑L1 TPS ≥1%): among 83 patients, confirmed ORR 4.8% (all partial responses); median PFS 2.1 months (95% CI 2.0–4.1); 27‑week DCR 31.3%. Recommended phase 2 dose (RP2D) 750 mg Q3W. (oncologypro.esmo.org)
CPI‑naïve cohorts:
PD‑L1 TPS 1–49%: ORR 29%; median PFS 6.0 months (95% CI 2.7–8.4); median DOR 6.4 months (95% CI 4.2–NC). (onclive.com)
PD‑L1 TPS ≥50%: ORR 61.8% (95% CI 43.6–77.8%); median PFS 10.2 months (95% CI 6.3–NC); median DOR 10.3 months (95% CI 8.2–NC). Data are from the first analysis of ARTEMIDE‑01 CPI‑naïve parts C/D and remain preliminary. (onclive.com)

Ongoing phase 3 studies (no efficacy readouts yet)

NSCLC: ARTEMIDE‑Lung03 compares rilvegostomig + platinum/pemetrexed vs pembrolizumab + platinum/pemetrexed in first‑line PD‑L1–positive metastatic non‑squamous NSCLC (started November 2024; target n≈878). (cdek.pharmacy.purdue.edu)
Biliary tract cancer (adjuvant): ARTEMIDE‑Biliary01 evaluates rilvegostomig + investigator’s‑choice chemotherapy (capecitabine, S‑1, or gemcitabine/cisplatin) vs placebo + chemotherapy; primary endpoint recurrence‑free survival (JCO abstract TPS4199; enrollment began 2024; planned n≈750). (ascopubs.org)
Hepatocellular carcinoma: ARTEMIDE‑HCC01 compares rilvegostomig + bevacizumab with or without tremelimumab vs atezolizumab + bevacizumab in first‑line advanced HCC (registered as NCT06921785; launched 2025; planned n≈1220). (smartpatients.com)
Gastric/GEJ (HER2+, PD‑L1 CPS ≥1): ARTEMIDE‑Gastric01 (phase 3) tests rilvegostomig + fluoropyrimidine + trastuzumab deruxtecan vs trastuzumab + chemotherapy + pembrolizumab (3‑arm design; recruiting). (cdek.pharmacy.purdue.edu)

Safety

CPI‑pretreated NSCLC (ARTEMIDE‑01 parts A/B): treatment‑related AEs in 54.2% (grade ≥3 in 8.4%); no grade 4/5 treatment‑related AEs; discontinuations 3.6%. (oncologypro.esmo.org)
CPI‑naïve NSCLC (ARTEMIDE‑01 parts C/D): grade ≥3 treatment‑related AEs 10.5%; treatment‑related discontinuations 4.2%; no clear safety differences between 750 mg and 1500 mg Q3W. (onclive.com)

Key trials (selection)

Phase I/II first‑in‑human NSCLC: ARTEMIDE‑01 (NCT04995523). (cdek.pharmacy.purdue.edu)
Phase III first‑line NSCLC: ARTEMIDE‑Lung03 (NCT06627647). (cdek.pharmacy.purdue.edu)
Phase III adjuvant BTC: ARTEMIDE‑Biliary01 (NCT06109779). (ascopubs.org)
Phase III first‑line HCC: ARTEMIDE‑HCC01 (NCT06921785). (smartpatients.com)
Phase III first‑line HER2+ gastric/GEJ: ARTEMIDE‑Gastric01 (NCT06764875). (cdek.pharmacy.purdue.edu)

HealthScout AI Analysis

Goal: Evaluate safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of trastuzumab deruxtecan (T-DXd) alone and in combination with chemotherapy and/or immunotherapy, and identify recommended regimens/doses for further development in HER2-expressing gastric, GEJ, and esophageal adenocarcinoma. The hypothesis is that T-DXd-based combinations will have manageable safety and show meaningful antitumor activity in first-line settings for HER2-positive and HER2-low disease.

Patients: Adults (≥18 years) with pathologically confirmed adenocarcinoma of stomach, gastroesophageal junction, or esophagus that is locally advanced unresectable or metastatic, measurable per RECIST v1.1, with adequate organ function. 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 progression after at least one trastuzumab-containing regimen; Parts 2–4 are previously untreated in the advanced/metastatic setting. Key exclusions include active or prior ILD/pneumonitis, uncontrolled illness or infection, significant effusions requiring drainage, spinal cord compression or active CNS metastases, and active viral infections (HIV, HBV, HCV).

Design: Multicenter, open-label, randomized, phase 1b/2 dose-escalation and dose-expansion study with multiple parallel experimental arms and an active comparator regimen. Approximately 413 participants will be assigned to T-DXd monotherapy or combinations versus standard trastuzumab plus fluoropyrimidine and platinum in relevant cohorts. Efficacy is assessed primarily by investigator-assessed RECIST v1.1 ORR in expansion parts; safety, DLTs, PK, and immunogenicity are emphasized in dose-escalation.

Treatments: Experimental regimens include: T-DXd alone; T-DXd plus 5-FU or capecitabine; T-DXd plus durvalumab; T-DXd plus pembrolizumab; triplets of T-DXd with fluoropyrimidine and durvalumab or pembrolizumab; T-DXd with capecitabine and oxaliplatin; and T-DXd with novel bispecific checkpoint inhibitors volrustomig (PD-1/CTLA-4) or rilvegostomig (PD-1/TIGIT), each combined with 5-FU or capecitabine. Active comparator: trastuzumab with fluoropyrimidine (5-FU or capecitabine) plus cisplatin or oxaliplatin, a standard first-line HER2-positive regimen. Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate targeting HER2 that delivers a topoisomerase I inhibitor payload with a high drug-to-antibody ratio and membrane-permeable payload enabling a bystander effect; it has demonstrated substantial activity in HER2-positive gastric cancer and activity in HER2-low disease in other tumor types, with ILD/pneumonitis as an important risk requiring monitoring. Volrustomig is a monovalent bispecific antibody targeting PD‑1 and CTLA‑4 on activated PD-1+ T cells, aiming to maximize intratumoral dual checkpoint blockade while limiting peripheral toxicity. Early-phase trials show encouraging response rates in RCC at doses ≤750 mg Q3W with lower grade 3–4 toxicity than higher doses; internalization/degradation of PD‑1 differentiates it mechanistically. Rilvegostomig is a humanized IgG1 bispecific antibody targeting PD‑1 and TIGIT with Fc modifications to reduce effector functions. Phase 1 data in pretreated NSCLC indicate acceptable tolerability at 750 mg Q3W with signals of activity and high peripheral receptor occupancy, supporting further development. Durvalumab and pembrolizumab are approved PD‑(L)1 inhibitors used across solid tumors; here they are evaluated in combination with T-DXd ± fluoropyrimidine to enhance antitumor immunity.

Outcomes: Primary outcomes: In Part 1, safety/tolerability including AEs/SAEs (CTCAE v5.0), DLTs, and changes in labs, vitals, and ECGs over approximately 24 months. In Parts 2–4, confirmed ORR by investigator per RECIST v1.1 at approximately 12 months. Key secondary outcomes: ORR in Part 1; safety endpoints in Parts 2–4; pharmacokinetics of T-DXd, total anti-HER2 antibody and released payload (MAAA-1181a), and of durvalumab, volrustomig, and rilvegostomig as applicable; anti-drug antibodies to relevant agents; DOR, DCR, PFS, and OS up to about 24 months; concordance analyses of efficacy endpoints by local versus central HER2 testing.

Burden on patient: Moderate to high. As a phase 1b/2 platform with multiple combination arms, participants can expect frequent clinic visits, intensive safety monitoring, serial labs, vitals, and ECGs, and periodic tumor imaging per RECIST. PK sampling for T-DXd and combination antibodies, as well as immunogenicity assessments (ADAs), add multiple blood draws, particularly early cycles. Infusional therapies (T-DXd, PD-1–based agents, and fluoropyrimidine infusions when 5-FU is used) require prolonged infusion visits and possible central venous access; capecitabine-based regimens reduce infusion time but still require monitoring. Risk of ILD/pneumonitis with T-DXd mandates additional evaluations for respiratory symptoms and potentially chest imaging. Overall visit and testing frequency exceeds standard first-line care due to dose-finding, PK, and safety assessments across arms.

Last updated: Oct 2025

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

Key trials (selection)

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

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