A phase 1/2 open-label, multicenter study to assess the safety, pharmacokinetics and anti-tumor activity of GTAEXS617 in patients with advanced solid tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Exscientia AI Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Jun 2023 → ongoing

Decision date (initial)

2024-01-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Exscientia AI Limited

External identifiers

EU CT number

2023-508227-13-00

EudraCT number

2022-003475-42

ClinicalTrials.gov

NCT05985655

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacokinetic, Safety

PHASE 1 & PHASE 2: To establish a preliminary optimal biologic dose (OBD)/recommended phase 2 dose (RP2D) of GTAEXS617 as monotherapy and in combination with selected SoC regimens
• To characterize the safety profile of GTAEXS617 as monotherapy and in combination with selected SoC regimens
PHASE 2 only:
• To evaluate preliminary anti-tumor activity of GTAEXS617, as measured by ORR, as monotherapy and in combination with selected SoC regimens [Phase 2]

Secondary objectives 3

1. PHASE 1 & PHASE 2: To characterize the PK of GTAEXS617 as monotherapy and in combination with selected SoC regimens
2. PHASE 1: To evaluate preliminary anti-tumor activity, as measured by ORR and other efficacy endpoints, of GTAEXS617 as monotherapy and in combination with selected SoC regimens
3. PHASE 2: To evaluate preliminary anti-tumor activity, as measured by other efficacy endpoints, of GTAEXS617 as monotherapy and in combination with selected SoC regimens

Conditions and MedDRA coding

Advanced solid tumors

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. 1. Aged ≥18 years at the time of signing the informed consent.
2. 4. Estimated life expectancy >3 months.
3. 5. Ability to swallow and retain oral medication.
4. 6. Adequate hematological, liver, and renal function defined below (repeated measurements of borderline values are permitted once): o Hemoglobin ≥8.5 g/dL. Any red blood count transfusion must have occurred at least 14 days prior to Screening. o Absolute neutrophil count ≥1.5 × 109/L. Any granulocyte colony-stimulating factor transfusion must have occurred at least 21 days prior to Screening.o Platelet count ≥150 × 109/L. Any platelet transfusion must have occurred at least 7 days prior to Screening. o Total bilirubin <1.5 × institutional upper limit of normal (ULN). Participants with known hepatobiliary metastases must have total bilirubin <2 × ULN. Participants with Gilbert’s Syndrome must have total bilirubin <3 × ULN and direct bilirubin ≤ULN. o ALT or AST ≤3 × ULN (or ≤5 × ULN if liver metastases are present). Creatinine clearance ≥60 mL/min based on the Cockcroft-Gault equation or method standard to institution.
5. 11. Participants must have advanced disease (i.e., unresectable, locally recurrent, or metastatic cancer) and had access to approved therapies.
6. Specific for HR+/HER2- Breast Cancer in Combination with Fulvestrant [Regimen C and Dose Expansion Cohort 3] 14. Confirmed diagnosis of HR+/HER2- metastatic breast cancer that has been treated with at least 1 line of therapy, and that has progressed following prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with hormonal therapy or was intolerant of the CDK 4/6 inhibitor.
7. 9. Measurable disease at baseline per RECIST 1.1 and documented by computed CT and/or MRI. Note: Lesions treated previously with radiation must demonstrate clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment.
8. 10. Female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) (as defined in Appendix A of the protocol) OR o A WOCBP who agrees to follow the contraceptive guidance in Appendix A during the treatment period and for at least 6 months after the final dose of study treatment. Exception: at least 2 years after the final dose of fulvestrant
9. 12. Participants must fulfill one of the following criteria: • Participant has progressed following available SoC treatments. • Participant has been removed from SoC treatment as they were unable to tolerate standard therapy • Participant is not a suitable candidate for SoC therapy. The Principal Investigator must document the reason that the participant is deemed not suitable for standard therapy. Participants who have been offered SoC therapies and refused may be eligible for this study Note: For participants in Phase 1 monotherapy and combination dose finding cohorts, there is no limit to the number of prior lines of treatments received.
10. 13. Specific for Phase 1 Monotherapy Dose 13. One of the following histologically or cytologically confirmed advanced solid tumors: HNSCC, pancreatic adenocarcinoma, NSCLC, breast carcinoma (HR+ and HER2- that has progressed to a prior treatment with CDK4/CDK6 inhibitor), or platinum-resistant HGSOC
11. 7. A nonsterilized male participant with female partners of reproductive potential must agree to use contraception during the treatment period and for at least 6 months after the final dose of the study treatment and must refrain from donating sperm during this period. Acceptable methods of contraception are defined in Appendix 2 of the protocol.
12. 8. Participant must have tumor lesion(s) or metastases amenable to biopsy, excluding bone metastases, as confirmed by a radiologist, if appropriate, and as deemed safe by the Investigator.
13. 2. Able and willing to provide written informed consent prior to start of any study-specific procedures.
14. 3. ECOG performance status 0-1.
15. Specific for Platinum Resistant HGSOC [Regimens A and B; Dose Expansion Cohorts 1 and 2] 15. Confirmed diagnosis of Platinum Resistant high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers (HGSOC) • Participants who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between >3 months and ≤6 months after the date last dose of platinum. • Participants who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum. • Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression. If a radiographic image is not available, the date of clinical progression in the opinion of the Investigator should be used • Note: Participants who are platinum-refractory during front-line treatment are excluded.
16. Specific for Platinum-resistant HGSOC in Phase 2 [Dose Expansion Cohorts 1 and 2] 16. Participants must have received no more than 2 lines in the platinum resistant setting and no more than 5 lines of systemic anti-cancer therapies in total. Additionally, for Phase 2-Monotherapy group only, single agent therapy is appropriate as the next line of treatment Guidance to assess total lines of therapy for platinum-resistant HGSOC: • Adjuvant ± neoadjuvant considered 1 line of therapy. • Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (i.e., not counted independently). • Therapy changed due to toxicity in the absence of progression will be considered part of the same line (i.e., not counted independently). • Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
17. Specific for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4] 17. Confirmed diagnosis of estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative which is defined for this study as <10% tumor staining by immunohistochemistry (IHC) from most recent tissue sample.
18. Specific for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4] 18. HER2-negative per current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 Guidelines (from most recent tissue sample)
19. Specific for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4] 19. Unresectable locally advanced or metastatic TNBC failed or relapsed after treatment with at least one line of standard chemotherapy regimens (taxanes and/or anthracyclines) or PD-L1 plus chemotherapy. For patients with documented germ line BRCA1/BRCA2 (breast cancer 1 gene/breast cancer 2 gene) mutations, PARP inhibitors can be considered as one of the previous standard therapies if they have been treated with approved PARP inhibitors

Exclusion criteria 42

1. 1. Any medical or psychiatric condition that, in the view of the Investigator, could jeopardize or would compromise the participant's safety or ability to participate in the study and make them unsuitable for participation.
2. 18. Current enrollment in another clinical study unless it is non-interventional or the follow-up period of an interventional study.
3. 19. Has had or is scheduled to have major surgery <28 days prior to the first dose of study treatment.
4. 2. Known hypersensitivity to any components of the study treatment or comparable drugs (drugs targeting CDK7).
5. 20. Active bleeding diathesis.
6. 21. International normalized ratio ≥1.5.
7. 3. Active and clinically significant (CS) infection requiring systemic antibacterial, antiviral, or antifungal therapy ≤7 days of the first scheduled dose of the study treatment.
8. 4. Known chronic or active infections with hepatitis B, hepatitis C, known human immunodeficiency virus, or acquired immunodeficiency syndrome related illness.
9. 5. Refractory nausea and/or vomiting, chronic gastrointestinal disease, or previous significant bowel resection, with CS sequelae that would preclude adequate absorption of GTAEXS617.
10. 6. Symptomatic central nervous system (CNS) malignancy or metastases. Screening of symptomatic participants without history of CNS metastases is not required. Participants with asymptomatic CNS lesions should have completed standard therapy for their CNS lesions 30 days prior to study enrollment, and be on a stable (non-tapering) dose of steroids.
11. 7. Concurrent active or previous malignancy (other than the primary malignancy for which the participant will be treated on this protocol – except for full resected squamous cell carcinoma of the skin, cervical carcinoma in situ or basal cell carcinoma) that could interfere with response evaluation.
12. 10. Received medications known to prolong QTc within 5 half-lives before the first dose of the study treatment. List of medications that prolong QTc can be obtained from crediblemeds.org.
13. 8. Prior organ or allogeneic stem-cell transplantation.
14. 9. Moderate or severe cardiovascular disease. o Presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension. o Documented major electrocardiogram (ECG) abnormalities at the Investigator’s discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree, atrioventricular block, bundle branch blocks, ventricular hypertrophy). o Participant has experienced any of the following during the last 6 months: coronary/peripheral bypass graft, cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or symptomatic pulmonary embolism.
15. 22. Participants with a history of (non-infectious) pneumonitis, or current pneumonitis/interstitial lung disease.
16. 23. Received treatment with systemic immunosuppressive medication (with the exception of the therapeutic use of steroids equivalent to prednisone ≤10mg/day) within 28 days or 5 half-lives (whichever is shorter) before the first dose of the study treatment.
17. 24. Known hypersensitivity to any components of fulvestrant (Specific Exclusion Criteria for Combination Therapy with Fulvestrant [Regimen C and Dose Expansion Cohort 3])
18. 25. Severe hepatic impairment (Child-Pugh class C). (Specific Exclusion Criteria for Combination Therapy with Fulvestrant [Regimen C and Dose Expansion Cohort 3])
19. 11. QTcF > 70 msec (average obtained from 3 ECGs) or history of torsades de pointes or history of congenital long QT syndrome. Patients with an apparent prolonged QT due to bundle branch block may be eligible on discussion with the Sponsor.
20. 12. Administration of a live vaccine within 28 days of starting study treatment and for up to 1 month after the final dose of study treatment or anticipation that such vaccine will be required during the study. Note: mRNA-based vaccines for COVID-19 are allowed as well as inactivated flu vaccines.
21. 13. Received anticancer therapy (with the exception of treatments defined in Section 6.8), including chemotherapy, immunotherapy, radiation therapy (with the exception of palliative radiotherapy), biologic therapy, cancer-related hormonal therapy, or any investigational therapy within 28 days or 5 half-lives (whichever is shorter) before the first dose of the study treatment.
22. 14. Received treatment with known strong and moderate inhibitors and/or strong inducers of cytochrome P450 3A isoform subfamily (CYP3A) within 14 days or 5 half-lives of the CYP3A modulator (whichever is longer) before the first dose of study treatment.
23. 15. Participants who have received treatment with known inhibitors or inducers of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) within 14 days or 5 half-lives of the drug (whichever is shorter) before the first dose of study treatment
24. 16. Participants who have received treatment with known substrates of organic anion transporting peptide 1B3 (OATP1B3) or BCRP within 14 days or 5 half-lives of the drug (whichever is longer) before the first dose of study treatment
25. 17. Unresolved or unstable toxic side-effects of prior chemotherapy or radiotherapy, except fatigue, alopecia, infertility, peripheral neuropathy or those relating to palliative radiotherapy within 6 weeks prior to first dose of study treatment must have resolved to Grade 1 or less.
26. 26. Known hypersensitivity to any components of paclitaxel and/or be(vacizumab. (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
27. 27. Severe hepatic impairment (Child-Pugh class C) (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
28. 28. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanized antibodies (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
29. 29. Prior treatment with paclitaxel / paclitaxel containing regimen in platinum resistant setting. (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
30. 30. Paclitaxel must not be used in participants with concurrent, serious uncontrolled infections. (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
31. 31. Participants with inadequate wound healing (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
32. 32. Participants who experienced any bleeding events, including hemoptysis, within 4 weeks prior to dosing or at high risk of bleeding including ovarian cancer patients who have evidence of recto-sigmoid involvement by pelvic exam or small bowel obstruction indicated by imaging or clinical symptoms. (Specific Exclusion Criteria for Combination Therapy with Paclitaxel + Bevacizumab [Regimen A])
33. 33. Known hypersensitivity to any components of doxorubicin, pegylated liposomal doxorubicin, peanut or soya, or any excipients including polyethylene glycol (PEG) and bevacizumab if added by investigator. Specific Exclusion Criteria for Combination Therapy with Pegylated liposomal doxorubicin [Regimen B]
34. 34. Prior treatment with pegylated liposomal doxorubicin and/or doxorubicin in the platinum-resistant setting. Specific Exclusion Criteria for Combination Therapy with Pegylated liposomal doxorubicin [Regimen B]
35. 35. Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or <50% by echocardiogram or MUGA Specific Exclusion Criteria for Combination Therapy with Pegylated liposomal doxorubicin [Regimen B]
36. 36. History of clinically significant congestive heart failure, recent myocardial infarction (within 6 months), uncontrolled arrhythmias, or unstable angina. Any other clinically significant cardiac disease that would increase the risk of anthracycline-induced cardiotoxicity. Specific Exclusion Criteria for Combination Therapy with Pegylated liposomal doxorubicin [Regimen B]
37. 37. History of severe and unexpected reactions to fluoropyrimidine therapy. Specific Exclusion for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4]
38. 38. Hypersensitivity to capecitabine or to any of its excipients or fluorouracil. Specific Exclusion for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4]
39. 39. Known complete dihydropyrimidine dehydrogenase (DPD) deficiency. Specific Exclusion for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4]
40. 40. Severe hepatic impairment (Child-Pugh class C) Specific Exclusion for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4]
41. 41. Treatment with brivudine within 4 weeks before the first dose of study treatment Specific Exclusion for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4]
42. 42. Prior treatment to capecitabine ≤12 months from first dose of study drug. Specific Exclusion for TNBC in Combination with Capecitabine [Regimen D and Dose Expansion Cohort 4]

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Incidence of DLTs during Cycle 1 of treatment (Phase 1)
2. Incidence and severity of AEs, SAEs and TEAEs; safety parameters variations from baseline (Phase 1)
3. Tolerability – Frequency of dose interruptions, dose reductions and dose intensity achieved (Phase 1)
4. ORR assessed using RECIST v1.1 (Phase 2)
5. Safety - Incidence and severity of AEs, SAEs and TEAEs; safety parameters variations from baseline (Phase 2)
6. Tolerability – Frequency of dose interruptions, dose reductions and dose intensity achieved (Phase 2)
7. Adherence – treatment diary(Phase 2)

Secondary endpoints 3

1. Plasma and urine GTAEXS617 PK parameters including but not limited to: • Cmax, tmax, AUC0-last, AUC(0-inf), AUC(0-tau), accumulation of Cmax (Rcmax) and AUC(0-tau) (RAUC(0-tau)), t1/2, CL/F, and Vz/F (Phase 1 and 2) • By-interval and cumulative GTAEXS617 excretion in urine (Ae and fe), and CLr
2. GTAEXS617 as monotherapy and in combination with SoC • Plasma GTAEXS617 PK concentrations and, if appropriate, plasma PK parameters DCR, PFS, and DOR, assessed using RECIST (Phase 1 and 2)
3. ORR, according to RECIST v1.1 Phase 1 (monotherapy & combination):

Investigational products

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

Test 32

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Exscientia AI Limited

Sponsor organisation

Exscientia AI Limited

Address

Level 3, 5 West Victoria Dock Road, 1 River Crescent 5 West Victoria Dock Road 1 River Crescent

City

Dundee

Postcode

DD2 1UJ

Country

United Kingdom

Scientific contact point

Organisation

Exscientia AI Limited

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Exscientia AI Limited

Contact name

Exscientia Information Desk

Third parties 13

Locations

1 EU/EEA country · 4 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 46 files

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

Application history

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