A study of AZD0901 alone or in combination with other anticancer drugs in patients with advanced/metastatic cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Nov 2024 → ongoing

Decision date (initial)

2024-09-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-508275-37-00

ClinicalTrials.gov

NCT06219941

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Efficacy, Safety, Dose response, Therapy

To investigate the safety and tolerability of AZD0901 monotherapy or in combination with anti-cancer agents in participants with advanced or metastatic solid tumours expressing CLDN18.2. To evaluate the preliminary anti-tumour activity of AZD0901 monotherapy or in combination with anti-cancer agents in participants with advanced or metastatic solid tumours expressing CLDN18.2 in terms of ORR.

Secondary objectives 4

1. Evaluate preliminary anti-tumour activity, characterise PK and determine immunogenicity of AZD0901 monotherapy or in combination with anti-cancer agents in participants with advanced or metastatic solid tumours expressing CLDN18.2 by assessment of OS, PFS, DoR, DCR, and % change in tumour size.
2. Sub study 1: Assess the change in intratumoural pharmacodynamic biomarkers following AZD0901 monotherapy
3. Sub study 1: Investigate baseline and/or on treatment-tissue-based RNA,DNA, and/or proteins, and association with clinical activity of AZD0901.
4. Substudy 3: Further evaluate the preliminary anti-tumour activity of AZD0901monotherapy by assessment of DRR.

Conditions and MedDRA coding

Gastric Cancer, Gastroesophageal Junction Cancer, Pancreatic Ductal Adenocarcinoma, Biliary Tract Cancer

Study design 5 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. both sub studies: Participant must be ≥ 18 years or the legal age of consent at the time of signing the ICF.
2. both sub studies: Participants who are CLDN18.2 positive. For participants who have received prior CLDN18.2 targeting therapies a new biopsy after treatment discontinuation must be provided to determine CLDN18.2 expression.
3. both sub studies: Must have at least one measurable lesion according to RECIST v.1.1.
4. both sub studies: ECOG performance status of 0 to 1 with no deterioration over the previous 2 weeks prior to first day of dosing.
5. both sub studies: life expectancy of ≥ 12 weeks.
6. both sub studies: Adequate organ and bone marrow function as defined by protocol.
7. both sub studies: Body weight > 35 kg.
8. both sub studies: Participants are willing to comply with contraception requirements.
9. Sub study 3: Histologically confirmed, unresectable advanced, or metastatic adenocarcinoma of biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma (Ampullary cancers are not eligible).
10. Sub study 3: Documented radiographic or clinical disease progression on or after at least one prior regimen and maximum 2 prior lines of systemic treatment for unresectable or metastatic disease.
11. Sub study 1: Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction.
12. Sub study 1: Advanced or metastatic GC/GEJC.
13. Sub study 1: The first approximately 30 participants in each arm are required to provide and archival sample up to 24 months old or a fresh tumour biopsy at screening. For participants enrolled after the first 30 in each arm, a fresh baseline biopsy is mandatory at screening, and on treatment biopsy is mandatory unless it is not clinically feasible.
14. Sub study 1: Maximum 2 prior lines of systemic treatment for unresectable or metastatic disease, including CLDN18.2 targeting mAbs (other prior CLDN18.2 targeting modalities are not allowed. Prior MMAE ADC are also not allowed). (a) Progression within 6 months/183 days of last dose of prior adjuvant or neoadjuvant therapy (including herceptin, immunotherapy) is considered as equivalent to progression on one regimen for advanced or metastatic disease. (b) If one of the components of prior combination therapy is discontinued due to AE and the other continued, this is considered to be ‘one prior regimen’. (c) If the prior therapy is discontinued due to poor tolerability or AE and the patient is switched to another therapy with no documented progression, this is considered to be ‘one prior regimen’. (d) Change in dose or route of administration (eg, IV or oral fluoropyrimidine) of prior regimen without progression is considered to be ‘one prior regimen’.
15. Sub study 2: Participants diagnosed with histologically confirmed metastatic or advanced PDAC.
16. Sub study 2: Availability of an archival sample up to 24 months old or a fresh tumour biopsy taken at screening.
17. Sub study 2: No prior treatments for unresectable or metastatic disease. Participants must not have received systemic therapy for mPDAC. Prior neoadjuvant/adjuvant chemotherapy is permitted as long as participants progressed ≥ 6 months from the last dose.
18. both sub studies: Participant with previously confirmed positive CLDN18.2 test result using the same assay in other AstraZeneca studies are eligible without prospective CLDN18.2 test at pre-screening.

Exclusion criteria 19

1. both sub studies: Unstable or active peptic ulcer disease or digestive tract bleeding including but not limited to clinically significant bleeding in the setting of prior CLDN18.2 directed therapy.
2. both sub studies: A history of drug-induced non-infectious ILD/pneumonitis. Participants with a history of radiation pneumonitis may be eligible. Investigator must discuss each case with the AstraZeneca Study Physician prior to enrolment.
3. both sub studies: Central nervous system metastases or CNS pathology. The following are exceptions to this criterion: (a) Participants with history of seizures are permitted if no active seizures in last 5 years. (b) Participants with brain metastases treated, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to the first dose of AZD0901.
4. both sub studies: Peripheral neuropathy, sensory, or motor, ≥ Grade 2 at screening
5. both sub studies: History of another primary malignancy except for: (a) Malignancy treated with curative intent with no known active disease for at least ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. (c) Adequately treated carcinoma in situ without evidence of disease. (d) Localised non-invasive primary disease under surveillance.
6. both sub studies: Prior exposure to any MMAE-based ADC.
7. both sub studies: Prior exposure to any CLDN18.2 targeted agents except anti-CLDN18.2 monoclonal antibody (eg. zolbetuximab).
8. Sub study 1: Participants with HER2-positive (3+ by IHC, or 2+ by IHC, and positive by ISH) or indeterminate GC/GEJC.
9. Sub study 3: Clinically significant biliary obstruction that has not resolved before enrolment
10. Sub study 1: Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age.
11. Sub study 1: The use of concomitant medications known to prolong the QT/QTc interval (refer to Section 6.9 for list of prohibited medications).
12. Sub study 2: Exclusion criterion 1 is specific for Arms 1, 1A, 1B and 1C (5FU specific). Exclusion criteria 2, 3, and 4 are specific for Arm 1 and Arm 1B (Irinotecan specific).
13. Sub study 2: Known DPD enzyme deficiency based on local testing where testing is SoC.
14. Sub study 2: Use of strong inhibitor or inducer of UGT1A1.
15. Sub study 2: Use of strong inhibitors or inducers of CYP3A4. Strong inducers of CYP3A4 should be stopped at least 2 weeks before and strong inhibitors of CYP3A4 should be stopped at least 1 week before the first dose of Irinotecan.
16. Sub study 2: Known homozygous for the UGT1A1*28 allele based on local testing where testing is SoC.
17. both sub studies: Participants with clinically significant ascites that require regular drainage.
18. Sub study 1: Participants randomised to treatment in study D9802C00001 (CLARITY-Gastric01).
19. both sub studies: Participants with reported weight loss >10% within one month from the most recent weight collection at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence of AEs and SAEs, Changes form baseline in laboratory parameters, vital signs, ECGs, and physical examination, Rate of AEs leading to discontinuation of AZD0901, Occurrence of DLTs (Japanese safety cohort in sub study 1, and safety run-in in sub study 2)
2. Proportion of participants with a confirmed Complete Response (CR) or Partial Response (PR) as determined by the Investigator at local site as per RECIST v1.1

Secondary endpoints 10

1. Overall Survival - The time from date of first dose/randomisation until the date of death due to any cause
2. Progression-free survival is defined as the time from first dose/date of randomisation until progression per RECIST v1.1 asassessed by the Investigator at local site, or death due to any cause, regardless of whether the participant withdraws from randomized therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST v1.1 progression.
3. DoR - The time from the date of first documented confirmed response until date of first documented progression per RECISTv1.1 or death due to any cause.
4. TTR - The time from first dose/date of randomisation until the first documentation of a subsequently confirmed objective response per RECIST v1.1 as assessed by the Investigator at local site.
5. DCR at 12 weeks is defined as the percentage of participants who have a confirmed CR or PR or who have SD per RECIST v1.1as assessed by the Investigator at local site and derived from the raw tumour data for at least 11 weeks after date of first dose/date of randomisation.
6. Tumor Size - The best percentage change from baseline in tumor size is the largest decrease (or smallest increase) from baseline for a participant, using RECIST v1.1 assessments.
7. To characterise the PK of AZD0901 monotherapy or in combination with anti cancer agents in participants with advancedor metastatic solid tumours expressing CLDN18.2.
8. To determine the immunogenicity of AZD0901 monotherapy or in combination with anti-cancer agents in participants with advanced or metastatic solid tumours expressing CLDN18.2.
9. To investigate baseline and/or on-treatment tissue-based RNA,DNA, and/or proteins, and association with clinical activity ofAZD0901 (substudy 1).
10. DRR-12: DRR-12 is defined as the percentage of subjects with a durable response at 12 weeks. DRR-24: DRR-24 is defined as the percentage of subjects with a durable response at 24 weeks.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 45 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications