Study of NMS-03305293 in Pts with Selected Advanced/Metastatic Solid Tumors

NCT04182516 | Terminated Phase 1 FDA Drug

• 2 other identifiers: PARPA-293-0012018-003918-40
• Study Type: interventional
• Target: 52
• Locations: 5 countries
• Sites: 10

Brief Summary

Phase I, first-in-human, open-label, multicenter, dose-escalation and dose expansion study with the aim of exploring safety, tolerability and preliminary antitumor activity of NMS-03305293 (a PARP inhibitor) as single agent in adult patients with selected advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options or for whom standard therapy is considered unsuitable.

Conditions

Advanced/Metastatic Solid Tumors

Keywords

HER2 negative breast cancer; Epithelial ovarian cancer; Castration-resistant prostate cancer (CRPC); Pancreatic cancer; BRCA1 Gene Mutation; BRCA2 Gene Mutation

Outcome Measures

Primary Outcomes (1)

• Number of Participants with first-cycle dose limiting toxicity

  Time interval between the date of the first dose administration in Cycle 1 (each cycle is 28 days) and the date of the first dose administration in Cycle 2 which is expected to be 28 days or up to 42 days in case of dose delay due to toxicity

Secondary Outcomes (14)

• Number of participants with Adverse Events (AEs)

  From the Informed Consent signature to 28 days after the last dose of study treatment administration.

• Maximum concentration (Cmax) of NMS-03305293 after single and multiple doses of drug

  Full PK : Schedule A, QD and BID dosing: Cycle 1, 2; Schedule B, QD and BID dosing: Cycle 1, 2 and 3. Sparse PK: Schedule A: and Schedule B Cycle 1, 2, 3 (last cycle and at each cycle from cycle 1 onwards).Cycle lenght is 4 weeks.

• Time to observed Cmax (Tmax) of NMS-033052293 after single and multiple doses of drug

  Full PK : Schedule A, QD and BID dosing: Cycle 1, 2; Schedule B, QD and BID dosing: Cycle 1, 2 and 3. Sparse PK: Schedule A: and Schedule B Cycle 1, 2, 3 (last cycle and at each cycle from cycle 1 onwards).Cycle lenght is 4 weeks.

• Area under the concentration-time curve to the last of measurable concentration (AUClast) of NMS-033052293 after single and repeated dose of drug.

  Full PK : Schedule A, QD and BID dosing: Cycle 1, 2; Schedule B, QD and BID dosing: Cycle 1, 2 and 3. Sparse PK: Schedule A: and Schedule B Cycle 1, 2, 3 (last cycle and at each cycle from cycle 1 onwards).Cycle lenght is 4 weeks.

• Terminal elimination half-life (t1/2) of NMS-033052293 after single and multiple doses of drug.

  Full PK : Schedule A, QD and BID dosing: Cycle 1, 2; Schedule B, QD and BID dosing: Cycle 1, 2 and 3. Sparse PK: Schedule A: and Schedule B Cycle 1, 2, 3 (last cycle and at each cycle from cycle 1 onwards).Cycle lenght is 4 weeks.

Study Arms (6)

Dose Escalation Part

EXPERIMENTAL

Patients with histologically confirmed diagnosis of locally advanced/metastatic HER2 negative breast cancer, epithelial ovarian cancer, castration-resistant prostate cancer (CRPC) or pancreatic cancer.

Drug: NMS-03305293

Dose Expansion Part - Epithelial Ovarian Cancer

EXPERIMENTAL

Patients with gBRCA mutation and epithelial ovarian cancer.

Drug: NMS-03305293

Dose Expansion Part - Pretreated HER 2 Neg. Breast Cancer

EXPERIMENTAL

Patients with gBRCA mutation and HER2 negative breast cancer previously treated with a PARP inhibitor.

Drug: NMS-03305293

Dose Expansion Part - No Pretreated HER 2 Neg. Breast Cancer

EXPERIMENTAL

Patients with gBRCA mutation and HER2 negative breast cancer who have not received prior therapy with a PARP inhibitor.

Drug: NMS-03305293

Dose Expansion Part - CRPC

EXPERIMENTAL

Patients with gBRCA mutation and castration-resistant prostate cancer (CRPC).

Drug: NMS-03305293

Dose Expansion Part - Pancreatic Cancer

EXPERIMENTAL

Patients with gBRCA mutation and pancreatic cancer who have not received prior therapy with a PARP inhibitor.

Drug: NMS-03305293

Interventions

NMS-03305293 DRUG

All patients will receive NMS-03305293 administered orally on Days 1-21 (schedule A) or Days 1-28 (schedule B) in repeated 4-week cycles.

Dose Escalation Part; Dose Expansion Part - CRPC; Dose Expansion Part - Epithelial Ovarian Cancer; Dose Expansion Part - No Pretreated HER 2 Neg. Breast Cancer; Dose Expansion Part - Pancreatic Cancer; Dose Expansion Part - Pretreated HER 2 Neg. Breast Cancer

Eligibility Criteria

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

You may qualify if:

• Patients with histologically confirmed diagnosis of locally advanced/metastatic HER2 negative breast cancer, epithelial ovarian cancer, castration-resistant prostate cancer (CRPC) or pancreatic cancer. BRCA1 and BRCA2 mutation status is not required for enrollment in the Dose Escalation part, but enrichment with deleterious/pathogenic or likely pathogenic/suspected deleterious BRCA carriers will be attempted.
• Patients must have progressive disease defined by RECIST 1.1 following standard therapy or be unsuitable for standard therapy. For CRPC patients, disease progression at study entry is defined as one or more of the following three criteria (according to PCWG2):
• PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2.0 ng/ml (µg/L). If the third PSA value is less than second PSA, a fourth PSA must be repeated and if the value is higher than second it must be considered as progressive disease;
• Soft tissue/visceral disease progression defined by RECIST 1.1;
• Bone disease progression defined by two or more new lesions on bone scan.
• Male or female patients with age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
• Life expectancy of at least 3 months.
• Signed and dated IEC or IRB-approved Informed Consent.
• At least 4 weeks must have elapsed or, in absence of toxicity, 5 half-lives, since completion of prior cancer therapy (at least 6 weeks for nitrosureas, mitomycin C and liposomal doxorubicin) before Cycle 1 Day 1.
• Adequate hematological profile, renal and hepatic functions.
• All patients must agree before enrollment to undergo germline BRCA1 and BRCA2 testing on blood. The test will be performed in a centralized laboratory selected by the sponsor. Availability of an ad hoc blood sample is mandatory for central germline BRCA analysis both in dose escalation and in dose expansion.
• Patients must use effective contraception or abstinence. Female patients of childbearing potential must agree to use effective contraception or abstinence during the period of therapy and in the following 6 months after discontinuation of study treatment. Being NMS-03305293 a potential CYP3A perpetrator, hormonal contraception may lose efficacy while on treatment with NMS-03305293, therefore this should be taken into account. Male patients must be surgically sterile or must agree to use effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment.
• Capability to swallow capsules intact (without chewing, crushing, or opening).
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures.

You may not qualify if:

• Current enrollment in another therapeutic clinical trial.
• Prior malignancy except for any of the following:
• Prior BRCA-associated cancer as long as there is no current evidence of the prior cancer;
• Carcinoma in situ or non-melanoma skin cancer;
• A cancer diagnosed and definitively treated ≥ 5 years before enrolment with no subsequent evidence of recurrence;
• Patients with prior platinum therapy exposure who had evidence of disease progression during platinum treatment (refractory disease) and patients whose disease relapsed within 6 months of the last dose of prior adjuvant or neo-adjuvant platinum therapy.
• Patients who have received prior PARP inhibitors are excluded in the following two cohorts of the Dose Expansion part: HER2 negative breast cancer patients not treated with prior PARP inhibitors and the pancreatic cancer patients cohort. Previous treatment with PARP inhibitors is allowed in the dose escalation part and in the expansion cohorts of ovarian cancer patients and CRPC patients.
• Patients with known symptomatic brain metastases or leptomeningeal involvement. Patients with asymptomatic brain metastases or leptomeningeal involvement are excluded in the Dose Escalation Part only.
• Treatment with systemic immune modulators such as corticosteroids at prednisone-equivalent dose of \>10 mg/day, cyclosporine and tacrolimus or radiotherapy within 28 days before Cycle 1 Day 1.
• Prior high-dose chemotherapy with bone marrow or stem cell transplant.
• Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment.
• Any of the following in the past 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis.
• Pregnancy or breast-feeding women.
• Known active infections (bacterial, fungal, viral including HIV positivity).
• Active gastrointestinal disease (e.g., documented gastrointestinal ulcer, Crohn's disease, ulcerative colitis, or short gut syndrome) or other syndromes that would impact on drug absorption.

Sponsors & Collaborators

• Nerviano Medical Sciences: lead

Study Sites (10)

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MHAT - Dobrich AD (Department of medical oncology)

Dobrich, Bulgaria

Location

MHAT Sveta Sofia EOOD (Department of medical oncology)

Sofia, Bulgaria

Location

MHAT Women's Health - Nadezhda OOD (Clinic of medical oncology)

Sofia, Bulgaria

Location

Fudan University Shanghai Cancer Center

Shanghai, China

Location

TianJin Medical University Cancer Institute & Hospital

Tianjin, China

Location

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Milan, 20123, Italy

Location

Istituto Oncologico Veneto IRCCS

Padua, 35128, Italy

Location

Centro Ricerche Cliniche di Verona Srl

Verona, 37134, Italy

Location

University College London Hospitals NHS Foundation Trust

London, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Ovarian Epithelial; Pancreatic Neoplasms

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Digestive System Neoplasms; Digestive System Diseases; Pancreatic Diseases

Study Officials

• Valentina Guarneri, MD

  Istituto Oncologico Veneto IRCCS

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Phase 1 Dose escalation part followed by a Dose Expansion part.

Study Record Dates

• First Submitted: November 12, 2019
• First Posted: December 2, 2019
• Study Start: November 25, 2019
• Primary Completion: March 31, 2023
• Study Completion: May 16, 2024
• Last Updated: September 19, 2024

Record last verified: 2024-09

Locations

IT (3); GB (1); BU (3); CN (2); US (1)