Combination Study of Guadecitabine/ASTX727 and Pembrolizumab

NCT02998567 | Recruiting Phase 1

• 1 other identifier: CCR4420
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

HyPeR is a multi-centre Phase 1 Dose Escalation Study of Guadecitabine (SGI-110)/ASTX727 a Second Generation Hypo-Methylating Agent in Combination with Pembrolizumab (MK3475) in Patients with Refractory Solid Tumours. The investigators will be investigating the safety and toxicity of the combination.

Conditions

Non Small Cell Lung Cancer

Keywords

immunotherapy; non small cell lung cancer

Outcome Measures

Primary Outcomes (2)

• Establish maximum tolerated dose (MTD)

  To establish a maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of guadecitabine and pembrolizumab in patients with advanced solid tumours. To determine the maximum dose at which no more than 1 of 6 patients at the same dose level experience a drug related toxicity (DLT), as defined in section 3.1.4 of the protocol.

  12 months

• Measure Adverse Events according to CTCAE v4.0

  To assess the safety and toxicity profile of the combination of guadecitabine and pembrolizumab. To determine causality and grading severity of each adverse event by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  24 months

Secondary Outcomes (7)

• Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.

  24 months

• Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.

  24 months

• Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.

  24 months

• Pharmacodynamic profile of guadecitabine in combination with pembrolizumab.

  24 months

• Pharmacodynamic studies in guadecitabine in combination with pembrolizumab.

  24 months

Other Outcomes (1)

• Preliminary assessment of the anti-tumour activity

  24 months

Study Arms (3)

Escalation

EXPERIMENTAL

Fixed dose of Pembrolizumab with escalating dose of Guadecitabine to establish the phase 2 recommended dose.

Drug: Guadecitabine; Drug: Pembrolizumab

Expansion

EXPERIMENTAL

Continuation of the Guadecitabine and Pembrolizumab dose established in arm 1: expansion in the recommended patient population.

Drug: Guadecitabine; Drug: Pembrolizumab

B2: Lung Expansion

EXPERIMENTAL

To further explore the safety and activity of the combination of ASTX727 (replacement of guadecitabine to an oral dose tablet) with pembrolizumab in patients with NSCLC with primary or secondary resistance to PD-1/PD-L1 inhibitors.

Drug: Pembrolizumab; Drug: ASTX727

Interventions

Guadecitabine DRUG

In arm 1 (escalation) and 2 (expansion).

Escalation; Expansion

Pembrolizumab DRUG

In arm 1 (escalation) and 2 (expansion).

B2: Lung Expansion; Escalation; Expansion

ASTX727 DRUG

In arm B2 (lung expansion) replacing guadecitabine

B2: Lung Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A and B1/2:
• Histologically or cytologically confirmed advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
• Part B1:
• Histologically or cytologically confirmed advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient AND:
• Patients with any tumour type that previously responded to a PD-1 or PD-L1 inhibitor and subsequently progressed (defined as secondary resistance to PD-1/PD-L1 inhibitors ie CR or PR by RECIST, or SD by RECIST for 6 months' duration) or/
• Patients with microsatellite-instability-high (MSI-High) tumours, provided they have been defined by validated assays or patients with deficient mismatch repair (dMMR) defined by immunohistochemistry, who have previously received and have progressed on a PD-1 or PD-L1 inhibitor (primary resistance to PD-1/PD-L1 inhibitors) or/
• Patients with other solid tumour types who could benefit, based on emerging anti-tumour activity data, from combination therapy with a demethylating agent and PD-1 or PD-L1 inhibitors, in consultation with any other relevant preclinical or clinical data, at the Chief Investigator's discretion.
• Part B2:
• Patients with histologically or cytologically confirmed NSCLC previously treated with PD-1 or PD-L1 inhibitor for advanced or metastatic disease.
• Life expectancy of at least 12 weeks.
• Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 with no significant deterioration over the previous 2 weeks (Appendix 1).
• Evaluable or measurable disease as assessed by RECIST 1.1.
• Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) prior to administration of any investigational medicinal product.
• Haemoglobin (Hb) ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 109/L

You may not qualify if:

• Radiotherapy (except brief course for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C and 4 weeks for investigational medicinal products) before treatment, except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with CRPC, which are permitted.
• Patient has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ bladder or cervical cancer that has undergone potentially curative therapy.
• Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
• Ongoing toxic manifestations of previous treatments. Exceptions to this are:
• Grade 1 toxicities, which in the opinion of the investigator should not exclude the patient
• Alopecia of any grade
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the chief Investigator.
• Has an active autoimmune disease that has required systemic treatment in past 3 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with Sjogren's syndrome will not be excluded from the study. In addition patients that experienced a Grade 2 or higher immune-related AE's on treatment with immunotherapy will be excluded from the study.
• Has evidence of interstitial lung disease.
• Has a history of (non-infectious) pneumonitis that required steroid treatment or has active pneumonitis. Pneumonitis includes acute interstitial pneumonitis, pneumonitis and idiopathic pneumonia syndrome.
• Active infection, requiring systemic therapy.
• Has received a live vaccine within 30 days of planned start of study therapy. Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
• Major surgery (excluding minor procedures, e.g. placement of vascular access) from which the patient has not yet recovered.
• At high medical risk because of severe or uncontrolled non-malignant systemic disease including active uncontrolled infection, active bleeding diathesis.
• Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Screening for chronic conditions is not required.

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Astex Pharmaceuticals, Inc.: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Institute of Cancer Research, United Kingdom: collaborator

Study Sites (2)

Royal Marsden Hospital

Sutton, Surrey, SM2 5PT, United Kingdom

RECRUITING

UCLH

London, W1T 7HA, United Kingdom

RECRUITING

Related Publications (1)

• Papadatos-Pastos D, Yuan W, Pal A, Crespo M, Ferreira A, Gurel B, Prout T, Ameratunga M, Chenard-Poirier M, Curcean A, Bertan C, Baker C, Miranda S, Masrour N, Chen W, Pereira R, Figueiredo I, Morilla R, Jenkins B, Zachariou A, Riisnaes R, Parmar M, Turner A, Carreira S, Yap C, Brown R, Tunariu N, Banerji U, Lopez J, de Bono J, Minchom A. Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors. J Immunother Cancer. 2022 Jun;10(6):e004495. doi: 10.1136/jitc-2022-004495.

  PMID: 35717027 BACKGROUND

Related Links

• Related Info

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

guadecitabine; pembrolizumab; decitabine and cedazuridine drug combination

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Central Study Contacts

Alexander Cowley, PhD

CONTACT

+44 (0) 20 3437 6927; alexander.cowley@icr.ac.uk

Anna Zachariou, PhD

CONTACT

anna.zachariou@icr.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2016
• First Posted: December 20, 2016
• Study Start: January 26, 2017
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: August 17, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)