A Phase I/II Study of MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors.

This is a phase I/II open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK) and antitumor activity of MEDI4736 in combination with olaparib in patients with advanced solid tumors, selected based on a rationale for response to olaparib.

Patients will be poly (adenosine diphosphate-ribose) polymerase (PARP)-inhibitor and immunotherapy (IMT)-naïve (defined as no prior exposure to PARP inhibitors or IMT, including, but not limited to, other anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], anti-programmed cell death 1 [PD-1], anti-programmed death-ligand 1 [PD-L1] monoclonal antibodies, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

The 4 initial stage cohorts (Modules 1 to 4) include patients with relapsed small cell lung cancer (SCLC), germline BRCA mutated (gBRCAm) metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer, gBRCAm platinum-sensitive relapsed ovarian cancer, and gastric cancer. The data cut-off occurred once all 4 Modules had reached last patient first visit (LPFV) + 2 years and all 4 cohorts had observed a median value for PFS.

Second stage cohorts (Modules 5 to 7) include patients with relapsed gBRCAm platinum-sensitive relapsed ovarian cancer and non gBRCAm platinum-sensitive relapsed ovarian cancer. The final data cut-off will be once Modules 6 and 7 have observed a median value for overall survival. At this timepoint, the clinical study database will close to new data.

Inclusion criteria

• Patients must have histologically or cytologically confirmed progressive advanced or metastatic solid tumor of one of the following:

• Platinum sensitive relapsed small cell lung cancer (module 1)
• gBRCAm HER2-negative metastatic breast cancer (module 2)
• gBRCAm ovarian cancer (modules 3 and 5)
• Metastatic or relapsed Gastric cancer (adenocarcinoma) (module 4)
• gBRCAm negative ovarian cancer (modules 6 and 7)
• At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (or magnetic resonance imaging [MRI] suitable for assessment as per RECIST 1.1. The baseline scan must be obtained within 28 days prior to the first dose of olaparib.
• Male or female patients, age ≥18 years (≥19 years for South Korea)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy ≥12 weeks
• Adequate organ and marrow function
• Ability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of olaparib, which is an oral agent. For the gastric cancer cohort, patients with a full or partial gastrectomy will be permitted.
• Ability of patient to understand and the willingness to sign a written informed consent document prior to any protocol related procedures, including screening evaluations.
• Female patients must either:

• Be of non-reproductive potential OR
• Have a negative serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1, and agree to use contraception if they or their partner are of reproductive potential

Exclusion criteria

• Prior chemotherapy or other systemic anticancer therapy within 4 weeks prior to start of olaparib treatment, 6 weeks for nitrosoureas or mitomycin. Exceptions include: Anti-hormonal treatment for ER positive or PR positive breast cancer is allowed until 7 days prior to treatment with olaparib, exposure to an investigational agent within 30 days or 5 half-lives (whichever is the longer) prior to start of olaparib treatment is not allowed, prior receipt of biologics targeting T cell co-regulatory proteins and/or immune checkpoints is not allowed. Examples include MEDI4736 or other PD1 or PD-L1 or PD-L2 inhibitors or anti-CTLA4 therapy, previous treatment with a PARP inhibitor, is not allowed.
• Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of treatment start.
• Current dependency on total parenteral nutrition or IV fluid hydration.
• Concomitant use of known strong cytochrome P450 (CYP) 3A (CYP3A) inhibitors or moderate CYP3A inhibitors. Concomitant use of known strong or moderate CYP3A inducers.
• Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation
• Whole blood transfusions in the last 120 days
• Patients with symptomatic or uncontrolled brain metastases.
• Patients being considered at poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease.
• Any psychiatric disorder that prohibits obtaining informed consent
• Major surgery or significant traumatic injury within 2 weeks of run-in
• Immunocompromised patients
• QTc prolongation >470 msec or other significant ECG abnormality noted within 14 days of treatment
• Pregnant and breastfeeding women are excluded.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Previous enrolment in the present study
• Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longer.