Clinical Trials /

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

NCT04182516

Description:

Phase I, first-in-human, open-label, multicenter, dose-escalation 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.

Related Conditions:
  • Breast Carcinoma
  • Ovarian Carcinoma
  • Pancreatic Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of NMS-03305293 in Pts With Selected Advanced/Metastatic Solid Tumors
  • Official Title: A Phase I Dose Escalation Study of NMS-03305293 in Adult Patients With Selected Advanced/Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: PARPA-293-001
  • SECONDARY ID: 2018-003918-40
  • NCT ID: NCT04182516

Conditions

  • Advanced/Metastatic Solid Tumors

Interventions

DrugSynonymsArms
NMS-03305293Dose Escalation Part

Purpose

Phase I, first-in-human, open-label, multicenter, dose-escalation 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.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation PartExperimentalPatients with histologically confirmed diagnosis of locally advanced/metastatic HER2 negative breast cancer, epithelial ovarian cancer, castration-resistant prostate cancer (CRPC) or pancreatic cancer.
  • NMS-03305293
Dose Expansion Part - Epithelial Ovarian CancerExperimentalPatients with gBRCA mutation and epithelial ovarian cancer previously treated with a PARP inhibitor.
  • NMS-03305293
Dose Expansion Part - Pretreated HER 2 Neg. Breast CancerExperimentalPatients with gBRCA mutation and HER2 negative breast cancer previously treated with a PARP inhibitor.
  • NMS-03305293
Dose Expansion Part - No Pretreated HER 2 Neg. Breast CancerExperimentalPatients with gBRCA mutation and HER2 negative breast cancer who have not received prior therapy with a PARP inhibitor.
  • NMS-03305293
Dose Expansion Part - CRPCExperimentalPatients with gBRCA mutation and castration-resistant prostate cancer (CRPC) who have not received prior therapy with a PARP inhibitor.
  • NMS-03305293
Dose Expansion Part - Pancreatic CancerExperimentalPatients with gBRCA mutation and pancreatic cancer who have not received prior therapy with a PARP inhibitor.
  • NMS-03305293

Eligibility Criteria

        Inclusion Criteria:

        Inclusion Criteria for Dose Escalation and Dose Expansion Part:

          1. Patients with histologically confirmed diagnosis of locally advanced/metastatic HER2
             negative breast cancer, epithelial ovarian cancer, castration-resistant prostate
             cancer (CRPC) or pancreatic cancer. BRCA mutation status is not required for
             enrollment in the Dose Escalation part, but enrichment with pathogenic BRCA carriers
             will be attempted.

          2. 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.

          3. Male or female patients with age ≥ 18 years.

          4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.

          5. Life expectancy of at least 3 months.

          6. Signed and dated IEC or IRB-approved Informed Consent.

          7. 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.

          8. Prior platinum therapy is allowed provided that criteria for platinum refractory
             disease are not met (see exclusion criterion n.3).

          9. Prior treatment with PARP inhibitors is allowed in the Dose Escalation Part and
             required in two Cohorts of the Dose Expansion Part (HER2 neg breast cancer and
             epithelial ovarian cancer with prior therapy with a PARP inhibitor). It is not allowed
             in the other cohorts of patients enrolled in the Dose Expansion.

         10. Resolution of all acute toxic effects (excluding alopecia) of any prior anticancer
             therapy to NCI CTC (Version 5.0) Grade ≤ 1 or to the baseline laboratory values as
             defined in Inclusion Criterion Number 11.

         11. Adequate hematological profile, renal and hepatic functions.

         12. 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.

         13. 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 90 days after discontinuation of study
             treatment. 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.

         14. Capability to swallow capsules intact (without chewing, crushing, or opening).

         15. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests and other study indications or procedures.

             Inclusion Criteria specific for Dose Expansion Part:

         16. Patients must have deleterious/pathogenic germline BRCA mutation confirmed by the
             centralized laboratory selected by the Sponsor.

         17. Measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1
             (RECIST) except for CRPC patient who can have non-measurable disease.

         18. Patients must have received the following previous treatment:

             - HER2 negative breast cancer: no more than 3 prior chemotherapy regimens for locally
             advanced and/or metastatic disease (no limit on prior hormonal therapies or targeted
             anticancer therapies). At least 1 line of taxane or anthracycline based chemotherapy,
             if not contraindicated, in adjuvant/neoadjuvant or metastatic setting.

             If HR (Hormone Receptor) positive, at least 1 line of prior endocrine therapy.

               -  Epithelial ovarian cancer: no more than 4 prior regimens for locally
                  advanced/metastatic disease including at least 1 line of platinum based
                  hemotherapy;

               -  CRPC: no more than 4 prior regimens; must have received at least 1 prior NHA
                  (e.g. abiraterone or enzalutamide) and a taxane. Ongoing androgen deprivation
                  therapy with a GnRH analogue or orchiectomy (i.e., surgical or medical
                  castration) is mandatory.

               -  Pancreatic cancer: no more than 2 prior regimens. Patients may have received
                  prior radiotherapies (not considered as a regimen).

         19. Patients with controlled, asymptomatic CNS involvement, which has been stable for the
             previous 4 weeks, are eligible. The use of seizure prophylaxis is allowed as long as
             patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs).

        Exclusion Criteria:

          1. Current enrollment in another therapeutic clinical trial.

          2. 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;

          3. 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.

          4. Patients who have received prior PARP inhibitors should be excluded in the Dose
             Expansion part except for the cohorts of HER2 negative breast cancer patients with
             prior PARP inhibitors and epithelial ovarian cancer patients with prior PARP
             inhibitors.

          5. Patients with symptomatic brain metastases or leptomeningeal involvement. Patients
             with asymptomatic brain metastases or leptomeningeal involvement are excluded in the
             Dose Escalation Part only.

          6. 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.

          7. Prior high-dose chemotherapy with bone marrow or stem cell transplant.

          8. Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment.

          9. 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.

         10. Pregnancy or breast-feeding women.

         11. Known active infections (bacterial, fungal, viral including HIV positivity).

         12. 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.

         13. Patients with QTc interval ≥ 480 milliseconds or with risk factors for torsade de
             pointes (e.g., heart failure, uncontrolled hypokalemia, family history of long QT
             syndrome) or receiving treatment with concomitant medications known to prolong the
             QT/QTc interval that cannot be replaced with another treatment.

         14. Patients receiving treatment with concomitant medications known to be CYP2D6 and
             CYP2C19 substrates with narrow therapeutic window that cannot be replaced with another
             treatment.

         15. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration or may interfere with the interpretation of study results and, in
             the judgment of the Investigator, would make the patient inappropriate for entry into
             this study or could compromise protocol objectives in the opinion of the Investigator
             and/or the Sponsor.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with first-cycle dose limiting toxicity
Time Frame: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of participants with Adverse Events (AEs)
Time Frame:From the Informed Consent signature to 28 days after the last dose of study treatment administration.
Safety Issue:
Description:Safety will be assessed by AEs, which includes abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induces clinical signs or symptoms, needs active intervention, interruption or discontinuation of the study drug or is medically significant. A treatment-emergent AE is defined as abnormal AE observed after starting administration of the study drug up to 28 days after last dose of study medication intake. AEs will be coded with Medical Dictionary for Regulatory Activities and graded according to The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Measure:Maximum concentration (Cmax) of NMS-03305293 after single and multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Time to observed Cmax (Tmax) of NMS-033052293 after single and multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints..
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Area under the concentration-time curve to the last of measurable concentration (AUClast) of NMS-033052293 after single and repeated dose of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Terminal elimination half-life (t1/2) of NMS-033052293 after single and multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Area under the plasma concentration vs. time curve to infinity (AUCinf) of NMS-033052293 after multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Accumulation ratio (Rac) of NMS-033052293 after multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Oral plasma clearance (CL/F) of NMS-033052293 after multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Apparent volume of distribution (Vd/F) of NMS-033052293 after multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 8, 15, 21, 22, 23 and 24 and Cycle 2 (Days 1, 8,15, 21) at different timepoints.ferent timepoints.
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments.
Measure:Renal clearance of NMS-033052293 after multiple doses of drug.
Time Frame:At baseline, at Cycle 1 (each cycle is 28 days) Day 1 and Day 21.
Safety Issue:
Description:Samples of urine will be used for pharmacokinetics assessments. In the dose escalation only: samples collected in all patients enrolled after the first DLT occurrence or starting the 4th dose level, whichever occurs first.
Measure:Objective tumor response (OR)
Time Frame:At baseline, every even cycle (Day 28), at the end of treatment and at follow-up, every 8 weeks, till disease progression, an average 18 months.
Safety Issue:
Description:Objective tumor response (OR) measured using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For prostate cancer patients response will be evaluated by RECIST version 1.1/PCWG3 for patients with measurable disease and by Prostatic Specific Antigen (PSA) for all patients through PCWG3 criteria.
Measure:Progression Free Survival (PFS)
Time Frame:From date of first dose of study drug up to the date of first documentation of disease progression or death due to any cause, whichever cames first, an average of 2 years.
Safety Issue:
Description:Progression Free Survival (PFS) will be calculated from the date of treatment initiation to the date of first documentation of disease progression according to RECIST 1.1 or RECIST 1.1/PCWG3 for patient with CRPC, or death due to any cause, whichever comes first.
Measure:Time To Progression (TTP)
Time Frame:From date of first dose of study drug up to the date of first documentation of disease progression or death due to progression, an average of 2 years.
Safety Issue:
Description:Time to Progression (TTP) will be evaluated from the date of treatment initiation to the date of first documentation of disease progression according to RECIST 1.1 criteria or RECIST 1.1/PCWG3 for patient with CRPC, or death due to progression, whichever comes first.
Measure:Time to PSA progression (for prostate cancer only)
Time Frame:From date of first dose of study drug up to the date of first documentation of PSA progression, an average of 1 year.
Safety Issue:
Description:Time to PSA Progression will be calculated from the date of treatment initiation to the date of first documentation of PSA progression according to PCWG3 criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nerviano Medical Sciences

Trial Keywords

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

Last Updated

November 28, 2019