Advanced Malignancies

Primary Objectives: Phase1: To characterize the safety and tolerability of isatuximab in combination with atezolizumab in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC), or recurrent glioblastoma multiforme (GBM), and to determine the recommended Phase 2 dose (RP2D). Phase2: To assess response rate (RR) of isatuximab in combination with atezolizumab in participants with HCC or SCCHN or EOC. Phase2: To assess the progression free survival rate at 6 months (PFS-6) of isatuximab in combination with atezolizumab, or as a single agent in participants with GBM. Secondary Objectives: To evaluate the safety profile of isatuximab monotherapy (GBM only), or in combination with atezolizumab in Phase 2. To evaluate the immunogenicity of isatuximab and atezolizumab. To characterize the pharmacokinetic (PK) profile of isatuximab single agent (GBM only) and atezolizumab in combination with isatuximab. To assess the overall efficacy of isatuximab in combination with atezolizumab, or single agent (GBM only).

Isatuximab

Isatuximab

Vial

20

Primary Outcome Measures :
Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 3 weeks after first study treatment administration ]
DLTs as observed during DLT-observation period

Adverse events (AEs) [ Time Frame: Up to 90 days after last study treatment administration (Up to approximately 27 months after first study treatment administration) ]
Number of patients with AEs based on standard and systematic assessment including changes in laboratory tests and vital signs, according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) version 4.03 Grade scaling

Maximum tolerated dose (MTD) [ Time Frame: Up to 3 weeks after first study treatment administration ]
MTD determined during Phase 1

Recommended Phase 2 dose (RP2D) [ Time Frame: Up to 3 weeks after first study treatment administration ]
Dose selected for the Phase 2 portion

Response Rate [ Time Frame: Up to 6 months after last patient's first treatment in a given cohort ]
In patients with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC) assessed by using RECIST 1.1

Progression free survival [ Time Frame: Up to 6 months after last patient's first treatment ]
In patients with glioblastoma multiforme (GBM) assessed by using Response Assessment for Neuro-Oncology (RANO) criteria at 6 months

INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
I 01. Participant must be at least 18 years of age, at the time of signing the informed consent.

Type of participant and disease characteristics
I 02. For HCC, SCCHN, and EOC, disease location amenable to mandatory tumor biopsy at
baseline (optional in Phase 1 and Phase 2 Stage 1, mandatory in Phase 2 Stage 2), and at
Cycle 2 Day 1 if clinically feasible. Fine needle aspirates are not acceptable. Needle or
excisional biopsies, or resected tissue are required. Provision of archival tumor tissue
sample obtained at the time of or after progression of immediate previous line of anticancer treatment is allowed to replace mandatory baseline biopsy. For GBM, it is optional
in Phase 1 and Phase 2 Stage 1, mandatory in Phase 2 Stage 2 to provide archival tumor
tissue sample. The biopsy taken at baseline and potentially Cycle 2 Day 1 should be from a
lesion not previously irradiated (preferred), or the new growth area of a lesion that grows
after irradiation.
I 03. At least one measurable lesion for HCC, SCCHN, EOC (per RECIST 1.1 [Appendix 11:
Section 10.11]). Tumor lesions previously irradiated, or received other locoregional
therapy, are usually not considered measurable unless there has been documented
progression in the lesion.
I 04. Based on the investigator’s judgement, at this time, other anti-cancer therapy is not the best
option for this specific patient.
For patients with HCC:
I 05. Histologically confirmed unresectable HCC (excluding fibrolamellar and mixed
hepatocellular/cholangiocarcinoma). Radiology diagnosed HCC as per American
Association for the Study of Liver Diseases criteria needs to be confirmed by histology
before initiation of IMP.
I 06. Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not
amenable to locoregional therapy or refractory to locoregional therapy, and not amenable
to a curative treatment approach
I 07. Child Pugh Class A liver score within 14 days of initiation of IMP (see Appendix 13:
Section 0).
I 08. Documentation of progressive disease (PD) during or after treatment with either sorafenib
or lenvatinib, or intolerance to the therapy. Intolerance is defined as permanent
discontinuation of sorafenib or lenvatinib due to occurrence of ≥CTCAE Grade 2
treatment-related adverse event (AE) which (1) persisted in spite of comprehensive
supportive therapy according to institutional standards AND (2) persisted or recurred after
sorafenib or lenvatinib treatment interruption of at least 7 days and dose reduction by one
dose level.
For patients with SCCHN:
I 09. Histologically confirmed recurrent or metastatic SCCHN (oral cavity, pharynx, larynx),
not amenable to local therapy with curative intent (surgery or radiation therapy with or
without chemotherapy).
I 10. Documentation of tumor recurrence or PD within 6 months of last platinum-based therapy
in primary (ie, unresectable locally advanced disease with radiation), recurrent, or
metastatic setting. Clinical progression after platinum-based therapy is defined as
progression of a lesion at least 10 mm in size that is amenable to caliper measurement
(eg, superficial skin lesion as per RECIST 1.1) or a lesion that has been visualized and
photographically recorded with measurements and shown to have progression are eligible.
I 11. Received and failed up to 2 lines of prior systemic anti-cancer therapy. A line of systemic
chemotherapy is defined as any chemotherapy that was administered as part of primary
therapy for SCCHN (eg, induction or concurrent chemo-radiatherapy) or any single-agent
or multiple-agent chemotherapy regimen that was administered after a diagnosis of
recurrent SCCHN.
I 12. Resting baseline O2 saturation by pulse oximetry of ≥92% at rest.
For patients with EOC:
I 13. Histologically confirmed advanced epithelial ovarian, fallopian tube, or peritoneal cancer,
excluding mucinous histology but including malignant mixed Müllerian tumors with high
grade serous component.
I 14. Received and failed up to 3 lines of prior platinum-containing therapy when the disease
was platinum-sensitive, and the patients should not have received any systemic therapy for
platinum-resistant/refractory disease. Platinum-resistant/refractory disease is defined as PD
within 6 months following the last administered dose of platinum-containing therapy
(resistant), or lack of response or disease progression while receiving the most recent
platinum-containing therapy (refractory), respectively. Previous treatment with up to one
line of PARP inhibitor therapy is allowed.
For patients with GBM:
I 15. Have histologically confirmed glioblastoma. Patients with the original histology as low
grade glioma are NOT eligible.
I 16. Documentation of PD or first recurrence during (after at least 12 weeks from completion of
irradiation) or after temozolomide maintenance therapy for newly diagnosed GBM treated
with 1st line radiotherapy plus concurrent temozolomide, unless the recurrence is outside
the radiation field or there is unequivocal histologic confirmation of tumor progression.
Patients who received additional surgery after first recurrence ARE eligible.
Sex
I 17. Male or Female
Informed Consent
I 18. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2)
which includes compliance with the requirements and restrictions listed in the informed
consent form (ICF) and in this protocol.

EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (for patients with
HCC, SCCHN, and EOC), or Karnofsky performance score of ≤70 (for patients with GBM
(see Appendix 14: Section 10.14)
E 02. Predicted life expectancy <3 months.
E 03. Active brain metastases or leptomeningeal metastases. Patients with asymptomatic central
nervous system metastases which have been stable (defined as without evidence of
progression by MRI for at least 28 days prior to initiation of IMP and any neurologic
symptoms have returned to baseline) following treatment with surgery or radiation therapy
are eligible.
E 04. Symptomatic or impending cord compression at study entry, unless appropriately treated
beforehand and remained clinically stable and asymptomatic.
E 05. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent for
patients with HCC, SCCHN, and EOC). Physiologic replacement doses are allowed even if
they are >10 mg of prednisone/day or equivalent, as long as they are not being administered for immunosuppressive intent. Inhaled or topical steroids are permitted,
provided that they are not for treatment of an autoimmune disorder.
E 06. Significant cardiac dysfunction such as New York Heart Association classification for
chronic heart failure III-IV, symptomatic coronary artery disease, major clinically
significant electrocardiogram (ECG) abnormality, clinically significant ventricular
arrhythmias; myocardial infarction within 6 months; unstable, poorly controlled angina
pectoris despite treatment.
For patients with SCCHN:
E 07. Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx, squamous
cell carcinoma of unknown primary, and salivary gland or non-squamous histologies (eg,
mucosal melanoma).
For patients with EOC:
E 08. Non-epithelial tumor or ovarian tumors with low malignant potential (ie, borderline
tumors, eg, low grade serous).
For patients with GBM:
E 09. Have more than 1 prior recurrence.
E 10. Presence of diffuse leptomeningeal disease or extracranial metastases.
E 11. Tumors primarily localized or originated from the brainstem or spinal cord.
E 12. Requires treatment with dexamethasone >4 mg/day, or bioequivalent for at least
3 consecutive days, within 2 weeks before initiation of IMP.
E 13. Mental impairment that may compromise ability to give informed consent and comply
with the requirements of the study.
E 14. Uncontrolled seizure by medication.
Prior/concomitant therapy
E 15. Prior treatment with an agent (approved or investigational) that blocks CD38 (patients who
had previously participated in a study with an anti-CD38 but have written confirmation
they were on control arm are allowed).
E 16. Prior treatment with an agent (approved or investigational) that blocks the PD-1/PD-L1
pathway (patients who had previously participated in a study with an anti-PD-1/PD-L1 but
have written confirmation they were on control arm are allowed).
E 17. Prior intravenous (IV) cytotoxic chemotherapy, antineoplastic biological therapy within
21 days from initiation of IMP, major surgery with 28 days from initiation of IMP; and prior oral cytotoxic chemotherapy, hormonal therapy, tyrosine kinase inhibitor therapy, or
completed palliative radiotherapy within 14 days from initiation of IMP.
For patients with GBM:
E 18. Received vascular endothelial growth factor (VEGF)/VEGF receptor directed therapy.
E 19. Locally directed therapies (except radiotherapy) including but not limited to stereotactic
radiosurgery, re-irradiation, Gliadel, and therapeutics administered by direct injection or
convection-enhanced delivery within 6 months before initiation of IMP.
Prior/concurrent clinical study experience
E 20. Last dose of prior investigational agent within 28 days from initiation of IMP.
Diagnostic assessments
E 21. Inadequate organ and bone marrow function at the Screening visit:
- White blood cell (WBC) <2000/mm3
(2.0 × 109
/L)
- Absolute neutrophil count (ANC) <1500/mm3
(1.5 × 109
/L)
- Platelets <100 × 109
/L for patients with SCCHN, EOC and GBM; or <75 × 109
/L for
patients with HCC. Platelet transfusion is not allowed within 7 days before the
screening hematological test
- Hemoglobin <9 g/dL or <5.6 mmol/L (without transfusion within 1 week )
- Total bilirubin >2 upper limit of normal (ULN)
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 × ULN
(or >5 × ULN for patients with liver metastases or HCC)
- For Phase 1, patients without pre-existing or acute liver disease (including viral
hepatitis, HCC or liver metastasis), total bilirubin >1.5 × ULN, AST and/or
ALT >2 × ULN, ALP >2.5 × ULN.
- International normalized ratio (INR) >1.7 or prothrombin time >4 seconds above
control for patients with HCC
- Albumin <2.8 g/dL for patients with HCC
- Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2
(Modification of Diet
in Renal Disease [MDRD] Formula)
E 22. Prior solid organ or bone marrow transplantation.
E 23. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory
agents (including but not limited to anti-CTLA4 mAbs) that caused permanent
discontinuation of the agent, or that were Grade 3 or 4 in severity, or that have not resolved
to baseline at least 3 months prior to initiation of IMP.
E 24. History of Grade 3 immune-mediated ADRs (eg, colitis, hepatitis, etc).
E 25. Ongoing AEs (excluding alopecia and fatigue) caused by any prior anti-cancer therapy
>Grade 1 (NCI-CTCAE v4.03).
E 26. Active, known, or suspected autoimmune disease.
E 27. History of or current interstitial lung disease or pneumonitis (radiation pneumonitis in the
radiation field is permitted); history of thoracic radiation received thoracic radiation
therapy of >30 Gy within 6 months of the first dose of trial treatment.
E 28. Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu
vaccines that do not contain live virus are permitted.
E 29. Known additional malignancy either progressing or requiring active treatment within the
last 3 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy).
E 30. Women of childbearing potential (WOCBP) or male patients with female partners of
childbearing potential not protected by highly effective method of birth control and/or who
are unwilling or unable to be tested for pregnancy (see Appendix 4: Section 10.4).
E 31. Pregnant or breastfeeding women or women who intend to become pregnant during
participation in the study.
E 32. Known intolerance or hypersensitivity to any component of isatuximab, atezolizumab, or
pre-medication.
E 33. History or current evidence of any condition, therapy, or laboratory abnormality that might
confound the results of the trial, interfere with the patient’s participation for the full
duration of the trial, or is not in the best interest of the patient to participate, in the opinion
of the treating Investigator.
E 34. Known uncontrolled HIV infection.
E 35. Known uncontrolled hepatitis B virus (HBV) infection:
• Anti-HBV therapy started before initiation of IMP and HBV viral load <2000 IU/mL
(104
copies/mL) are eligible. The anti-HBV therapy should continue throughout the
treatment period
• Positive anti-HBc, anti-HBs, negative HBsAg, and HBV virus load without HBV
therapy are eligible
For patients with HCC:
E 36. Esophageal or gastric variceal bleeding within the past 12 weeks.
E 37. Clinically apparent ascites on physical examination. Ascites detectable on imaging studies
only ARE eligible.
E 38. Complete portal vein or inferior vena cava occlusion, or cardiac involvement of HCC
based on imaging.
E 39. Clinically diagnosed hepatic encephalopathy within 3 months before initiation of IMP.
E 40. Prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib or
lenvatinib.
E 41. Locoregional therapy to liver (transcatheter chemoembolization, transcatheter
embolization, hepatic arterial infusion, radiation, radioembolization, or ablation) within
4 weeks before initiation of IMP.