| Eligibility |
Inclusion Criteria:
1. =18 years of age inclusive, at the time of signing the informed consent.
2. Capable of giving signed informed consent, which includes compliance with the
requirements of this protocol.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. For patients
with NHL, ECOG 2 will be allowed.
4. Patients with histologically or cytologically confirmed advanced or metastatic
malignancies (including histologically confirmed, unresectable Stage III or IV
melanoma); see following details for each malignancy:
For Patients with cutaneous and mucosal melanoma:
1. Baseline lactate dehydrogenase levels are available.
2. Disease progression is confirmed and they are eligible for second- or third-line
treatment:
- After first-line treatment and progression on approved programmed cell
death-1 (PD-1) or cytotoxic T lymphocyte antigen-4 (CTLA-4) or combination
of PD-1 and CTLA-4-pathway targeted agent.
- After second-line treatment and progression on prior BRAF V600 mutation
targeted agent followed by PD-1 or CTLA-4-pathway targeted agent (Note:
There is no mandatory sequence of these approved treatments).
3. No clinically significant tumour-related symptoms.
For Patients with metastatic ocular/uveal melanoma:
Patients must have metastatic histologically or cytologically confirmed uveal
melanoma.
For Patients with advanced or metastatic mesothelioma:
1. Histological confirmation of mesothelioma (any subtype).
2. Part A: They received at least one prior line of treatment (including patients
who were re-challenged with pemetrexed-based therapy). Prior maintenance therapy
is permitted but will not count as a line of treatment.
Part B: Considered for first-line treatment with pemetrexed/cisplatin and avelumab.
For Patients with Indolent Non-Hodgkin Lymphoma, type Follicular Lymphoma (FL):
1. Patients must have a past diagnosis of indolent Non-Hodgkin lymphoma, type
Follicular Lymphoma, Grade 1-3A.(Dreyling et al., 2016)
2. Patients must have been previously treated with at least 1 prior systemic
chemotherapy, immunotherapy, or chemoimmunotherapy, such as rituximab
monotherapy, chemotherapy given with or without rituximab, radioimmunoconjugates
(e.g., 90Y-ibritumomab tiuxetan and 131I-tositumomab).
3. Must have documented relapsed, refractory, or PD after treatment with systemic
therapy (refractory defined as less than PR or disease progression <6 months
after last dose).
4. Patients with prior exposure to a PI3K inhibitor (e.g., idelalisib/GS-1101,
duvelisib) or a Bruton's tyrosine kinase (BTK) inhibitor are eligible if they
discontinued either inhibitors in the last 4 weeks prior entering study
treatment.
5. Patients are not eligible for transplantation (autologous or any similar
intervention, including CART-cell therapy).
For Patients with Non-Hodgkin Lymphoma, type Peripheral T cell lymphoma (PTCL):
1. Diagnosis of one of the following histologic subtypes of PTCL,
pathologically-confirmed, as defined by the World Health Organization (other rare
PTCL may be enrolled upon discussion with the medical monitor of this study):
- Peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS)
- Angioimmunoblastic T-cell lymphomas (AITL)
- Anaplastic large cell lymphoma (ALCL)
- Natural-killer/T-cell lymphoma (NKTL)
2. Received at least 2 cycles of one prior regimen administered with curative intent
and one of the following:
- failed to achieve at least a partial response after 2 or more cycles;
- failed to achieve a complete response after 6 or more cycles; and/or
- progressed after an initial response.
3. For patients with CD30+ ALCL, failed or are ineligible or intolerant to
brentuximab vedotin.
4. Measurable disease as defined by IWG for PTCL, i.e., at least 1 measurable
disease lesion > 1.5 cm in at least one dimension by 18FDG-PET-CT, MRI, or
diagnostic CT.
5. Patients with prior exposure to a PI3K inhibitor (e.g., idelalisib/GS-1101,
duvelisib) or a Bruton's tyrosine kinase (BTK) inhibitor are eligible if they
discontinued either inhibitors in the last 4 weeks prior entering study
treatment.
For Patients with Non-Small Cell Lung Cancer (NSCLC) 1st line:
1. Histological diagnosis of locally advanced (primary or recurrent) NSCLC
non-squamous not amenable for treatment with curative intent.
2. No prior systemic treatment for unresectable locally advanced or metastatic
disease for NSCLC.
3. Non-squamous NSCLC, with no activating EGFR mutations, ALK or ROS1
translocations/rearrangements.
4. If monotherapy pembrolizumab is available as a standard of care treatment option,
patients must have a tumour proportion score (TPS) <50% for PD-L1 (e.g., via the
22C3 pharmDx or the Ventana (SP263) PD-L1 IHC assay, or any other approved IHC
assay.
For Patients with Non-Small Cell Lung Cancer (NSCLC) 2nd or 3rd line:
1. Histological confirmed Stage IIIb/IV or recurrent NSCLC who have experienced
disease progression.
2. Considered for 2nd line or 3rd line treatment either after radiographic
progression or on stable disease:
- Participants must have progressed after a minimum of 2 cycles of 1 course of
a platinum based combination therapy administered for the treatment of a
metastatic disease.
For Patients with Primary Myelofibrosis (PMF):
1. Diagnosis of PMF, Post-Polycythemia Vera Myelofibrosis MF(PPV-MF), or
post-essential thrombocythemia MF (PET-MF)
2. Dynamic International Prognostic Scoring System (DIPSS) risk category of
intermediate-1, intermediate-2, or high.
3. Treated with ruxolitinib for = 3 months with a stable dose for at least the last
8 weeks prior to Day 1 and no significant spleen reduction (e.g., less than 15%
spleen size reduction, or corresponding lack of response in spleen volume).
4. Did not receive experimental drug therapy for MF or any other drug considered as
an effective treatment for MF (eg, danazol, hydroxyurea, interferon products)
within the last 2 months prior to starting study treatment.
5. Splenic irradiation within 6 months before receiving the first dose of study
drug.
6. Independent of spleen size. active symptoms of MF at the screening visit, as
demonstrated by the presence of a Total Symptom Score (TSS) of = 10 using the
Screening Symptom Form.
7. Screening bone marrow biopsy specimen and pathology report(s) available that was
obtained no more than 2 months prior to starting the study treatment or
willingness to undergo a bone marrow biopsy at screening/baseline; willingness to
undergo bone marrow biopsy at Week 24 and every 24 weeks thereafter.
Screening/baseline biopsy specimen must show diagnosis of MF.
8. Peripheral blast count < 10%.
9. Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives
(whichever is longer) before the first dose of study drug or anticipated during
the study.
5. Presence of measurable disease per RECIST v.1.1, or mRECIST (for cohort with pleural
mesothelioma patients), as determined by the site study team. Tumour lesions situated
in a previously irradiated area are considered measurable if progression has been
demonstrated in such lesions.
For NHL (FL and PTCL) patients: Have measurable disease as defined by the Lugano
Classification, including at least one lymph node or tumour mass greater than or equal
to 1.5 cm.
For PMF patients: Have measurable disease as defined by IWG-MRT criteria.
6. For patients with prior systemic therapies (Groups 1, 2, 6, and 7) disease progression
must be reported after available therapies for advanced or metastatic disease that are
known to confer clinical benefit, been intolerant to treatment, or refused standard
treatment. Within 6 months and prior to entering the study, a patient who has
completed an adjuvant, neo-adjuvant, or chemo-radiation regimens would be considered
of having received 1 prior systemic regimen and would not require an additional
systemic regimen for advanced or metastatic disease.
7. Willingness to undergo a pre-treatment and on-treatment tumour biopsy to obtain the
specimen (for NHL and PMF: see respective requirements).
Note: If a patient has signed the informed consent and is scheduled to have a tumour
biopsy for the purposes of this study, and it is subsequently determined that tumour
tissue cannot safely be obtained, the patient may still enrol in the study, and the
patient may be replaced, if enrolled in Part A, after discussion between the Sponsor
and Investigator. The patient will be replaced if enrolled in Part B. However, all
patients will be part of the final safety PK, PD (except for the examinations related
to the pre- and post-dosing biopsy) and efficacy evaluation.
8. Willingness to avoid pregnancy or fathering children based on the criteria below:
1. Women of non-childbearing potential (i.e., surgically sterile with a hysterectomy
and/or bilateral oophorectomy OR = 12 months of amenorrhea and at least 50 years
of age).
2. Women of childbearing potential who had a negative serum pregnancy test at
screening and who agree to take appropriate precautions to avoid pregnancy (with
at least 99% certainty) from screening through safety follow-up, at least 1 month
after the last dose of study treatment. Women receiving cisplatin should not
become pregnant for at least 6 months after receiving the last dose of cisplatin.
Permitted methods that are at least 99% effective in preventing pregnancy should
be communicated to the patient and their understanding confirmed.
3. Men who agree to take appropriate precautions to avoid fathering children (with
at least 99% certainty) from screening through safety follow-up, at least 1 month
after the last dose of study treatment. Men receiving pemetrexed and/or cisplatin
should not father within 6 months of last treatment with pemetrexed and/or
cisplatin. Permitted methods that are at least 99% effective in preventing
pregnancy (see should be communicated to the patient and their understanding
confirmed.
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