DZR123 (CPI-0209) in Patients with Advanced Solid Tumors and Lymphomas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Oct 2021 → ongoing

Decision date (initial)

2024-04-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-508002-20-00

EudraCT number

2020-004952-14

WHO UTN

U1111-1307-0794

ClinicalTrials.gov

NCT04104776

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

Phase 1 (DZR123 Monotherapy Dose Escalation):
Determine maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of DZR123 as monotherapy in patients with advanced tumors

Phase 2 (DZR123 Monotherapy Dose Expansion and Dose Optimization):
Evaluate the antitumor activity of DZR123 as monotherapy in patients with selected advanced solid tumors and lymphomas

Cohort M8 Part 1 (DZR123 and Enzalutamide Combination Dose Escalation in Patients with mCRPC):
Determine the RP2D of DZR123 in combination with enzalutamide

Cohort M8 Part 2 (DZR123 and Enzalutamide Combination Dose Expansion in Patients with mCRPC):
Evaluate the antitumor activity of DZR123 in combination with enzalutamide.

Secondary objectives 4

1. Phase 1 (DZR123 Monotherapy Dose Escalation): Characterize the safety and tolerability of DZR123 as monotherapy. Phase 2 (DZR123 Monotherapy Dose Expansion and Dose Optimization): Further characterize the safety and tolerability of DZR123 as monotherapy in patients with selected advanced solid tumors and lymphomas. Cohort M8 Part 1 (DZR123 and Enzalutamide Combination Dose Escalation in Patients with mCRPC): Characterize the safety and tolerability of DZR123 in combination with enzalutamide including safety and tolerability of enzalutamide in run-in period. Cohort M8 Part 2 (DZR123 and Enzalutamide Combination Dose Expansion in Patients with mCRPC): Further characterize the safety and tolerability of DZR123 in combination with enzalutamide including safety and tolerability of enzalutamide in run-in period.
2. Phase 1 (DZR123 Monotherapy Dose Escalation): Characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of DZR123 as monotherapy. Phase 2 (DZR123 Monotherapy Dose Expansion and Dose Optimization): Further characterize the PK and PD profile of DZR123 as monotherapy. Cohort M8 Part 1 (DZR123 and Enzalutamide Combination Dose Escalation in Patients with mCRPC): Characterize the PK and PD profile of DZR123 and enzalutamide. Cohort M8 Part 2 (DZR123 and Enzalutamide Combination Dose Expansion in Patients with mCRPC): Further characterize the PK and PD profile of DZR123 and enzalutamide.
3. Phase 1 (DZR123 Monotherapy Dose Escalation): Evaluate the preliminary clinical activity of DZR123 as monotherapy in patients with advanced tumors. Phase 2 (DZR123 Monotherapy Dose Expansion and Dose Optimization): Assess the optimal dose for future clinical trials. Cohort M8 Part 1 ( DZR123 and Enzalutamide Combination Dose Escalation in Patients with mCRPC): Evaluate the preliminary clinical activity of DZR123 in combination with enzalutamide i Cohort M8 Part 2 ( DZR123 and Enzalutamide Combination Dose Expansion in Patients with mCRPC): Further evaluate the clinical activity of DZR123in combination with enzalutamide
4. Phase 2 DZR123 Monotherapy Dose Expansion and Dose Optimization): Cohort M7 only: Evaluate the effect of a HFHC meal on the PK behavior of DZR123 monotherapy at 300 mg dose in patients with ARID1A WT endometrial carcinoma. Cohort M8 Part 1 DZR123and Enzalutamide Combination Dose Escalation in Patients with mCRPC): Establish dose-toxicity relationship of DZR123 and enzalutamide combination

Conditions and MedDRA coding

advanced, solid, relapsed tumors / advanced tumors: human lymphomas / solid human tumor indications (urothelial carcinoma, or other advanced/metastatic solid tumors, ovarian clear cell cancer, endometrial carcinoma, lymphoma including peripheral T-cell Lymphoma and GCBDLBCL, malignant pleural or peritoneal mesothelioma, metastatic castration - resistant prostate cancer (mCRPC))

Study design 7 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Adult (aged ≥ 18 years)
2. 2. Have a life expectancy of ≥ 12 weeks
3. Provide a baseline archival tumor sample (Phase 1); for Phase 2, provide a fresh or archival tumor biopsy at baseline, except as noted for Cohort M4 and Cohort M6. Refer to Section 6.2.11 and Section 6.2.12.
4. Must be willing to provide blood and tumor samples for central biomarker testing
5. Recovered to baseline or Grade ≤ 1 severity from toxicity related to prior treatments, unless AEs are clinically non-significant and/or stable on supportive therapy
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7. Adequate bone marrow function defined by the following hematological parameters: +Solid tumor patients: - absolute neutrophil count (ANC) of ≥ 1.5 × 10^9/L, without growth factor support (filgrastim or pegfilgrastim) for at least 14 days - platelet count of ≥ 100×10^9/L - hemoglobin of ≥ 9.0 g/dL (with or without transfusion) + Lymphoma patients with documented bone marrow involvement: - ANC ≥ 0.75 × 10^9/L, without growth factor support (filgrastim or pegfilgrastim) for at least 14 days - platelet count of ≥ 75 x 10^9/L, without platelet transfusion for at least 14 days - hemoglobin ≥ 9.0 g/dL (with or without transfusion)
8. Adequate renal function defined as creatinine clearance > 30 mL/min for patients with creatinine levels above institutional normal as determined by Cockcroft-Gault equation OR serum creatinine ≤ 1.5 × the upper limit of normal (ULN)
9. Adequate hepatic function defined as serum total bilirubin ≤ 1.5 × ULN, AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases); for patients who have known Gilbert’s disease with total bilirubin < 3 × ULN may be eligible provided that the treating physician does not consider it clinically significant.
10. Male and female patients and their partners with childbearing potential should agree to use at least one of the highly effective contraceptive methods listed in Section 6.12.1.1 while on study therapy and for 93 days after the last dose of DZR123 for male patients and male partners of female patients, and for 183 days- after the last dose of DZR123 for female patients and female partners of male patients. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
11. Signed and dated institutional review board (IRB)/independent ethics committee (IEC) approved informed consent form (ICF) before any protocol-directed screening procedures are performed.
12. P1:adults with confirmed locally advanced or metastatic tumors (solid tumors or lymphoma) who have relapsed after or progressed through standard therapy or who have a disease with no standard effective therapy P2, M1: a Confirmed, locally advanced, unresectable or metastatic UC with predominant urothelial histology b confirmed metastatic solid tumor (except OCCC, EC, and pleural or peritoneal mesothelioma) c Known ARID1A mutation d Disease progression during or following prior chemotherapy approved therapies or for which no standard therapy exists) e Measurable disease per RECIST1.1 M2:adults with Confirmed advanced OCCC b ARID1A mutation c received min.1 line of PCC and bevacizumab d Measurable disease per RECIST1.1 e Pt must have PD after receiving effective and available SoC treatment for CCOC M3:adults with Confirmed recurrent, metastatic, or unresectable EC b Known ARID1A mutation c Min.1 line of PCC in recurrent/metastatic setting d documented MSI-high or, dMMR or non-dMMR/microsatellite stable tumors should have received prior anti-PD-1 or anti-PD-L1 therapy e Brachytherapy is allowed if completed >12wks before 1st dose of study drug f Measurable disease per RECIST1.1 g Pt must have received effective and available SoC treatment for EC M4: adults with lymphoma: a Confirmed PTCL or DLBCL with following criteria: PTCL: Documented refractory, relapsed, or PD after min.1 prior line of systemic therapy. Must have min.1 prior line of systemic therapy for PTCL o Pts must be considered HCT ineligible during screening due to disease status (active disease), comorbidities, other factors o In PTCL, pts with ALCL must have prior brentuximab vedotin treatment DLBCL: Relapsed/refractory disease following 2 or more prior lines of SoC therapy Not considered candidates to receive CAR-T or ASCT as assessed by the treating investigator For pts with past ASCT or CAR-T treatment, min.90 days must have elapsed since start of the procedure. For all other pts, min.8 wks must have elapsed since most recent systemic anti-DLBCL therapy b Min.1 bi-dimensionally measurable lesion on imaging scan defined as >1. 5cm in its longest dimension M5: a Pleural or peritoneal relapsed/refractory mesothelioma b Must have progressed on or after min.1 prior line of active therapy c Have measurable disease for pleural mesothelioma (modified RECIST1.1) or for peritoneal mesothelioma (RECIST1.1) d. Known BAP1 loss per IHC or NGS testing M6:adults with mCRPC: a Have measurable soft-tissue disease with CT scan as defined by PCWG3 criteria b Documented metastatic disease c Progression while on prior therapies d Baseline testosterone levels must be ≤50 ng/dL (≤2.0 nM), surgical or ongoing medical castration must be maintained throughout the study M7: a confirmed recurrent, metastatic, or unresectable EC b Known ARID1A wildtype status and up to 5 pts with known TP53 alterations (both confirmed by NGS testing) c Received max. 2 prior lines of systemic therapy for metastatic/recurrent EC incl min. 1 line platinum-based regimen and anti-PD-1 or anti-PD-L1 agent alone or in combination unless these are contraindicated or are not locally accessible d Measurable disease per RECIST 1.1 M8: pts with prostate cancer with metastatic disease documented by bone and/or measurable soft tissue/visceral disease as per PCWG3 criteria, M8 Part 1 only: must have received min.1 ARPi (excl. enzalutamide) treatment in mCRPC or HSPC disease stage. M8 Part 2 only: must have received abiratoerone treatment in mCRPC or HSPC disease stage. For M8 Part 1 only: max 1 previous regimen of taxane-based chemotherapy in mCRPC or HSPC setting. For M8 Part 2 only: max 1 previous regimen of taxane-based chemotherapy in HSPC. For M8 Part 1 and M8 Part 2: pts with prostate cancer progression (per PCWG3) and ongoing ADT with a GnRH analogue, antagonist or bilateral orchiectomy, have baseline testosterone levels ≤ 50 ng/dL (≤ 2.0 nM), have surgical or ongoing medical castration

Exclusion criteria 13

1. Previous solid organ or allogeneic HCT.
2. Clinically active or symptomatic viral hepatitis or chronic liver disease.
3. Unstable or severe uncontrolled medical condition or any important medical or psychiatric illness or abnormal laboratory finding that would, in the Investigator’s judgment, increase the risk to the patient associated with his or her participation in the study.
4. Known symptomatic untreated brain metastases. Patients with CNS metastases must have stable neurologic status following local therapy for at least 4 weeks on stable or decreasing dose of steroid ≤ 10 mg daily prednisone (or equivalent). Patients in the M4 lymphoma cohort will not be eligible if they have known CNS involvement by lymphoma.
5. Clinically significant cardiovascular disease including: a. Myocardial infarction/stroke within 3 months prior (6 months for M8 cohort) to Day 1 of treatment. b. Unstable angina within 3 months (6 months for M8 cohort) prior to Day 1 of treatment. c. Congestive heart failure or cardiomyopathy with New York Heart Association (NYHA; see APPENDIX 3) Class 3 or 4. d. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes). e. Uncontrolled hypertension (as defined per institutional standards) despite 2 concomitant antihypertensive therapies. f. For Cohorts M1-M6: QT interval corrected by the Fridericia correction formula (QTcF) ≥ 480 msec on the Screening ECG. For Cohort M7 and M8: QTcF interval ≥450 msec at screening
6. Major surgery within 4 weeks before starting study drug or not recovered from any effects of prior major surgery (uncomplicated central line placement or fine needle aspirate are not considered major surgery).
7. Gastrointestinal disorders, ie, ulcerative colitis, malabsorption syndrome, refractory nausea and vomiting, biliary shunt, significant bowel resection, or any other condition that may significantly interfere with absorption of the study medication by Investigator’s assessment.
8. Uncontrolled active infection requiring intravenous antibiotic, antiviral, or antifungal medications within 14 days before the first dose of study drug. Infections (eg, urinary tract infection) controlled on concurrent antimicrobial agents and antimicrobial prophylaxis per institutional guidelines are acceptable.
9. Suspected pneumonitis or interstitial lung disease (confirmed by radiography or CT) or a history of pneumonitis or interstitial lung disease.
10. Have a history of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years. Patients with a history of T-cell lymphoblastic lymphoma or T-cell lymphoblastic leukemia are not eligible.
11. Have current known active or chronic infection with HIV, hepatitis B, or hepatitis C. Screening of patients with serologic testing for these viruses is not required. However, patients who have a past history of viral hepatitis or in whom there is a current suspicion of viral hepatitis should have serologic testing for hepatitis B and hepatitis C performed to determine whether there is any current evidence for ongoing infection with these viruses. Patients considered to be at risk for HIV infection should have HIV testing performed.
12. For Cohort M7 Only: Patients not willing to or cannot remain fasted due to a medical condition for 2 hours before and 1 hour after the dose administration.
13. For Cohort M8 only: - Biochemical recurrence/prostate-PSA-only disease - ONLY FOR M8 PART 1: Patients who received prior enzalutamide. ONLY FOR M8 PART 2: Patients who received prior enzalutamide, apalutamide, darolutamide or any other investigational ARPi. - Herbal products that may decrease PSA levels within 4 weeks prior to Day 1 of treatment and while on study - Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery. - Treatment with any investigational agent within 4 weeks before Day 1 of M8 Part 1 or M8 Part 2. - Prior irradiation to >25% of the bone marrow. - Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed. - History of seizure, loss of consciousness or transient ischemic attack within (12 months of study entry), or any condition that may predispose to seizure (e.g., stroke, brain arteriovenous malformation, head trauma, underlying brain injury).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. DZR123 Monotherapy Phase 1 and Cohort M8 Part 1 Occurrence of Dose-limiting toxicities during the 1st treatment cycle DZR123 Monotherapy Phase 2 ORR: proportion of pts with a BOR of CR or PR as per RECIST 1.1 (pts with solid tumors or peritoneal mesothelioma), 2014 Lugano criteria (pts with lymphoma), Modified RECIST 1.1 criteria (pts with pleural mesothelioma), PCWG3 criteria and per Investigator assessment (pts with prostate cancer including Cohort M8 Part 2)

Secondary endpoints 9

1. DZR123 Monotherapy Phase 1: Adverse events (AEs) and change in laboratory values. DZR123 Monotherapy Phase 2: PFS: the time from first dose to confirmed disease progression or death. Cohort M8 Part 1 and Cohort M8 Part 2: Incidence of AEs characterized by type, severity (graded by NCI CTCAE effective version), timing, seriousness and relationship to DZR123 and enzalutamide combination treatment.
2. DZR123 Monotherapy Phase 1 PK and PD parameters DZR123 Monotherapy Phase 2 Time-to-progression Cohort M8 Part 1 Pharmacokinetics: plasma concentration-time profiles and standard pharmacokinetic parameters including but not limited to Cmax, Tmax, AUC0-last, AUC0-inf, t1/2, Cmin. Cohort M8 Part 2 Pharmacokinetics: plasma concentration-time profiles and standard pharmacokinetic parameters including but not limited to Cmax, Tmax, AUC0-last, AUC0-inf, t1/2, Cmin.
3. DZR123 Monotherapy Phase 1 ORR:proportion of patients with a BOR of CR or PR, per Investigator assessment based on RECIST 1.1 or applicable response criteria DZR123 Monotherapy Phase 2 DOR:the time from the date of first response to the date of confirmed disease progression Cohort M8 Part 1 Change of pharmacodynamic biomarkers from baseline Cohort M8 Part 2 Change of pharmacodynamic biomarkers from baseline
4. DZR123 Monotherapy Phase 1 ORR per Gynecologic Cancer Intergroup (GCIG)-defined CA-125 response criteria (ovarian cancer patients) DZR123 Monotherapy Phase 2 TTR, defined as the time from first dose to date of first response Cohort M8 Part 1 Objective response, per Investigator assessment based on PCWG3 Cohort M8 Part 2 DOR, defined as the time from the date of first response to the date of confirmed disease progression.
5. DZR123 Monotherapy Phase 1: ORR per PCWG3 (in Phase 1 prostate cancer patients only) DZR123 Monotherapy Phase 2 Disease control rate: the proportion of patients with a BOR of CR, PR, or SD per cohort and DZR123 dose level Cohort M8 Part 1 DOR: the time from the date of first response to the date of disease progression per PCWG3 Cohort M8 Part 2 Progression-free survival (PFS) as per PCWG3 and defined as the time from first dose to confirmed disease progression or death
6. DZR123 Monotherapy Phase 1 Progression-free survival (PFS), defined as the time from first dose to confirmed disease progression or death DZR123 Monotherapy Phase 2 ORR per GCIG-defined CA-125 response criteria (ovarian cancer patients) Cohort M8 Part 1 Disease control defined as best overall response of CR, PR, or stable disease (SD) per PCWG3. Cohort M8 Part 2 Proportion of patients with PSA response ≥50%.
7. DZR123 Monotherapy Phase 1 DOR, defined as the time from the date of first response to the date of confirmed disease progression DZR123 Monotherapy Phase 2 Overall survival (OS), defined as the time from first dose to death Cohort M8 Part 1 PSA50 response, defined as PSA decline by >=50% from baseline. Cohort M8 Part 2 Time to PSA progression.
8. DZR123 Monotherapy Phase 1 Time to response (TTR), defined as the time from first dose to date of first response DZR123 Monotherapy Phase 2 AEs and changes in laboratory values Cohort M8 Part 1 Probability of DLT over dose range Cohort M8 Part 2 Overall survival (OS), defined as the time from first dose to death in patients with mCRPC
9. DZR123 Monotherapy Phase 1 Disease control rate, defined as the proportion of patients with a best overall response of CR, PR, or stable disease (SD) DZR123 Monotherapy Phase 2 9. PK and PD parameters In Cohort M7 only: PK parameters of DZR123 monotherapy at 300 mg dose with and without a HFHC meal in patients with ARID1A WT endometrial carcinoma

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 13

Locations

4 EU/EEA countries · 37 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 70 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