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.
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
- 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
- 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).
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
- 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
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
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
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.