A Dose Escalation Study of Adavosertib (MK-1775) in Combination With Either Gemcitabine, Cisplatin, or Carboplatin in Adults With Advanced Solid Tumors (MK-1775-001)
Condition: Solid Tumors
MeSH terms: Neoplasms
Intervention: adavosertib; gemcitabine; cisplatin; carboplatin
Intervention description: adavosertib administered as an oral formulation as either monotherapy or in combination with either gemcitabine, cisplatin, or carboplatin.; Gemcitabine administered at 1000 mg/m^2 by IV infusion in a 28-day cycle.; Cisplatin administered at 75 mg/m^2 by IV infusion in a 21-day cycle.; Carboplatin administered at AUC/time curve of 5 mg/min/mL (AUC5) by IV infusion in a 21-day cycle.
Intervention MeSH terms: Carboplatin; Gemcitabine; Adavosertib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 206.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study will investigate the safety, tolerability, pharmacokinetic (PK), and
      pharmacodynamic (PD) activity of adavosertib, both as monotherapy and in combination with
      gemcitabine, cisplatin, or carboplatin in participants with advanced solid tumors. Dose
      limiting toxicities (DLT) of adavosertib in combination with gemcitabine, cisplatin, or
      carboplatin will also be assessed. The primary hypotheses of the study are as follows: 1)
      Oral administration of adavosertib both as monotherapy and in combination with either
      gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors will be safe
      and tolerable, 2) The side effects observed in participants with advanced solid tumors after
      administration of adavosertib combined with each of the chemotherapies (gemcitabine,
      cisplatin and carboplatin) will allow for the definition of a single dose combination Maximum
      Administered Dose (MAD)/Maximum Tolerated Dose (MTD) and a multiple dose combination
      Biologically Effective Dose (BED)/MTD for each of the 3 combinations, 3) At a tolerated dose,
      adavosertib plasma exposure will exceed target thresholds established in preclinical models,
      and 4) At a tolerated dose, PD markers of adavosertib activity in combination with either
      gemcitabine, cisplatin, or carboplatin (in surrogate tissue and/or tumor) will meet or exceed
      the target threshold established in preclinical models.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have a histologically confirmed metastatic or locally advanced solid tumor,
             progressed despite standard therapy, or for which standard therapy does not exist

          -  Must have performance status of <=1 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale

          -  Female participants must not be pregnant

        Exclusion Criteria:

          -  Has had chemotherapy, radiotherapy, or biological therapy within 4 weeks prior to
             entering the study or who has not recovered from adverse events due to agents given
             more than 4 weeks earlier

          -  Is participating or has participated in a study with an investigational compound or
             device within 30 days

          -  Has active central nervous system (CNS) metastases and/or carcinomatous meningitis.
             However, participants with CNS metastases who have completed a course of therapy would
             be eligible for the study provided they are clinically stable for 1 month prior to
             entry

          -  Has a primary central nervous system tumor

          -  Is allergic to any of the components of the combination study therapy or its analogs

          -  Participant has had prescription or non-prescription drugs or other products known to
             be metabolized by Cytochrome P450 3A4 (CYP3A4) that cannot be discontinued prior to
             Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of
             study medication. Medications of particular concern are inhibitors of CYP3A4 (azole
             antifungals [ketoconazole, itraconazole], macrolide antibiotics [erythromycin,
             clarithromycin], cimetidine, aprepitant, Human Immunodeficiency Virus (HIV) protease
             inhibitors, nefrazodone, and the following inducers of CYP3A4: phenytoin, barbiturates
             and rifampicin, and substrates of CYP3A4 including statins (lovastatin, simvastatin),
             midazolam, terfenadine, astemizole, and cisapride

          -  Is a regular user (including "recreational use") of any illicit drugs or had a recent
             history (within the last year) of drug or alcohol abuse

          -  Pregnant or breastfeeding, or expecting to get pregnant during the time the study will
             be ongoing

          -  HIV-positive

          -  History of Hepatitis B or C

          -  Has symptomatic ascites or pleural effusion. A participant who is clinically stable
             following treatment for these conditions is eligible

          -  Participant must not have prior radiation therapy to more than 30% of the bone marrow
             and must have recovered for at least 3 weeks from the hematologic toxicity of prior
             radiotherapy

          -  Has had a prior stem cell or bone marrow transplant

          -  Has received more than 4 prior cytotoxic chemotherapy regimens

          -  Has a history suggestive of Li-Fraumeni Syndrome