Study to Evaluate CCS1477 in Haematological Malignancies

Study Overview
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Brief Summary
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A Phase 1/2a study to assess the safety, tolerability, PK and biological activity of CCS1477 in patients with Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukaemia or High Risk Myelodysplastic syndrome.

Detailed Description
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This includes patients with Peripheral T-cell lymphoma.

Official Title
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An Open-label Phase I/IIa Study to Evaluate the Safety and Efficacy of CCS1477 as Monotherapy and in Combination in Patients With Advanced Haematological Malignancies.

Conditions
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Haematological Malignancy, Acute Myeloid Leukemia, Non Hodgkin Lymphoma, Multiple Myeloma, Higher-risk Myelodysplastic Syndrome, Peripheral T Cell Lymphoma

Intervention / Treatment
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* Drug: CCS1477
* Drug: Pomalidomide
* Drug: Dexamethasone
* Drug: Azacitidine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of consent ECOG performance status 0-2 Patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (NHL, MM and AML) Must have previously received standard therapy Adequate organ function Exclusion Criteria: Intervention with any chemotherapy, investigational agents or other anti-cancer drugs within 14 days or 5 half-lives of the first dose Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study treatment Strong inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment Strong inducers of CYP3A4 within 4 weeks of the first dose of study treatment Patients should discontinue statins prior to starting study treatment CYP2C8 substrates with a narrow therapeutic range taken within 2 weeks of the first dose of study treatment Any unresolved reversible toxicities from prior therapy >CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2 neuropathy) Any evidence of severe or uncontrolled systemic diseases Any known uncontrolled inter-current illness QTcF prolongation (> 480 msec)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The RP2D/MTD dose will be determined in Parts A and B. Parts C, D, E and F of the study may recruit patients concurrently.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CCS1477 dose escalation NHL/MM<br>CCS1477 monotherapy | Drug: CCS1477<br>* Oral capsule<br>|
| Experimental: CCS1477 dose escalation AML/Higher risk MDS<br>CCS1477 monotherapy | Drug: CCS1477<br>* Oral capsule<br>|
| Experimental: CCS1477 expansion phase NHL/Peripheral T-cell lymphoma<br>CCS1477 monotherapy | Drug: CCS1477<br>* Oral capsule<br>|
| Experimental: CCS1477 monotherapy expansion and combination dose finding and expansion - MM<br>CCS1477 monotherapy, CCS1477 combination with pomalidomide-dexamethasone | Drug: CCS1477<br>* Oral capsule<br>Drug: Pomalidomide<br>* oral capsule<br>Drug: Dexamethasone<br>* oral tablet<br>|
| Experimental: CCS1477 monotherapy expansion and combination dose finding and expansion - AML<br>CCS1477 monotherapy, CCS1477 combination with azacitidine, CCS1477 combination with azacitidine and venetoclax | Drug: CCS1477<br>* Oral capsule<br>Drug: Azacitidine<br>* Powder suspension for Injection<br>Drug: Venetoclax<br>* Oral tablet<br>|
| Experimental: CCS1477 monotherapy expansion and combination dose finding and expansion - Higher risk MDS<br>CCS1477 monotherapy, CCS1477 combination with azacitidine, CCS1477 combination with azacitidine and venetoclax | Drug: CCS1477<br>* Oral capsule<br>Drug: Azacitidine<br>* Powder suspension for Injection<br>Drug: Venetoclax<br>* Oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-related adverse events | Treatment-related adverse events and serious adverse events | Up to 12 months | 
| Incidence of laboratory abnormalities | Laboratory abnormalities characterised by type, frequency, severity and timing | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Defined as number of patients who have a response according to RECIL criteria (NHL) IMWG criteria (Multiple myeloma) ELN recommendations 2017 (AML) | Up to 12 months | 
| Duration of Response | Defined as the time from start of treatment until disease progression | Up to 12 months | 
| AUC of CCS1477 | Area under the plasma concentration-time curve (AUC) from time 0 to the time of the last measurable concentration of CCS1477 | 35 days | 
| Cmax of CCS1477 | Maximum observed plasma concentration (Cmax) of CCS1477 | 35 days |